Mk2 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 62/051,788, filed Sep. 17, 2014 and 62/199,927, filed Jul. 31, 2015,the entirety of each of which is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of MK2kinases. The invention also provides pharmaceutically acceptablecompositions comprising compounds of the present invention and methodsof using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 isan important intracellular regulator of the production of cytokines,such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) andinterferon gamma (IFNγ), that are involved in many acute and chronicinflammatory diseases, e.g. rheumatoid arthritis and inflammatory boweldisease. M K2 resides in the nucleus of non-stimulated cells and uponstimulation, it translocates to the cytoplasm and phosphorylates andactivates tuberin and HSP27. MK2 is also implicated in heart failure,brain ischemic injury, the regulation of stress resistance and theproduction of TNF-α. (see Deak et al., EMBO. 17:4426-4441 (1998); Shi etal., Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin.Pharmacol. 4:372-377 (2004), and Shiroto et al., J. Mol. Cardiol.38:93-97 (2005)).

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimnmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there remains a need to find protein kinase inhibitorsuseful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of MK2. Such compounds have general formula I:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,T, R^(a), R¹, R², and R³, with respect to the formula I above, is asdefined and described in embodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with abnormal cellular responsestriggered by protein kinase-mediated events. Such diseases, disorders,or conditions include those described herein.

Compounds provided by this invention are also useful for the study ofkinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention:

In certain embodiments, the present invention provides irreversibleinhibitors of MK2. In some embodiments, such compounds include those ofthe formulae described herein, or a pharmaceutically acceptable saltthereof, wherein each variable is as defined and described herein.

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ring A is phenyl or a 5-6 membered heteroaryl ring having 1-3        nitrogens;    -   T is a bivalent moiety selected from —N(R)—, —O—, —S—, —S(O)—,        —SO₂—, —C(S)—, —Si(R⁴)₂—, —P(R⁵)—, —P(O)₂—, or a bivalent        saturated straight or branched 1-3 membered hydrocarbon chain,        wherein the hydrocarbon chain is optionally substituted with oxo        or —OR;    -   each R is independently hydrogen or an optionally substituted        C₁₋₆ aliphatic, or:        -   two R groups on the same nitrogen are taken together with            the nitrogen to form a 3-7 membered saturated or partially            unsaturated heterocyclic ring having 1-3 heteroatoms            selected from nitrogen, oxygen, or sulfur;    -   R^(a) is hydrogen or an optionally substituted C₁₋₆ aliphatic;    -   R¹ is —R or —(CH₂)_(p)R^(x);    -   p is 0, 1, 2, or 3;    -   R^(x) is —CN, —NO₂, halogen, —OR, —SR, —N(R)₂, —C(O)N(R)₂,        —C(O)OR, —C(O)R, —N(R)C(O)R, —SO₂N(R)₂, or —N(R)SO₂;    -   R² is halogen, —CN, —SR^(y), —S(O)R^(y), —SO₂R^(y), —OSO₂R^(y),        —OC(O)R^(y), or —OP(O)₂OR^(y);    -   each R^(y) is independently selected from optionally substituted        C₁₋₆ aliphatic or optionally substituted phenyl;    -   R³ is hydrogen, optionally substituted C₁₋₆ aliphatic, —CN,        —NO₂, halogen, —OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy,        —C(O)N(R)-Cy, —C(O)-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy,        —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy, —(CH₂)_(n)—N(R)-Cy, or        —(CH₂)_(m)-Cy;    -   each R⁴ is independently hydrogen, —OR, C₁₋₆ aliphatic, phenyl,        or a 5-6 membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   each R⁵ is independently —OR, C₁₋₆ aliphatic, phenyl, or a 5-6        membered heteroaryl ring having 1-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;    -   each of m and n is independently 0-4; and    -   each Cy is independently an optionally substituted ring selected        from a 3-9 membered saturated or partially unsaturated        monocyclic carbocyclic ring, a 3-9 membered saturated or        partially unsaturated monocyclic heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, phenyl, a 5-6 membered heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, a 7-12 membered saturated or partially unsaturated fused        or bridged bicyclic carbocyclic ring, or a 7-12 membered        saturated or partially unsaturated fused or bridged bicyclic        heterocyclic ring having 1-3 heteroatoms independently selected        from nitrogen, oxygen, and sulfur.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule. Unless otherwise specified, aliphatic groups contain 1-6aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-5 aliphatic carbon atoms. In other embodiments, aliphatic groupscontain 1-4 aliphatic carbon atoms. In still other embodiments,aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet otherembodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Insome embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or“cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system andexemplary groups include phenyl, biphenyl, naphthyl, anthracyl and thelike, which may bear one or more substituents. Also included within thescope of the term “aryl,” as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyi, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 T electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Exemplary heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Exemplary groups include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals includetetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthr-idinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group may have asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR)R^(∘);—(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂;—OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O (“oxo”), ═S,═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*,—O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independent occurrenceof R* is selected from hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents thatare bound to vicinal substitutable carbons of an “optionallysubstituted” group include: —O(CR₂)₂₋₃O—, wherein each independentoccurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which may besubstituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†), —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein each R^(†)is independently hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfnate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, Ring A(R²)(R³), of a provided compoundcomprises one or more deuterium atoms.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of activity of a protein kinase, for example, MK2 or a mutantthereof, in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ transplantation,biological specimen storage, and biological assays.

As used herein, a “disease or disorder associated with MK2” or,alternatively, “an MK2-mediated disease or disorder” means any diseaseor other deleterious condition in which MK2, or a mutant thereof, isknown or suspected to play a role.

The term “subject”, as used herein, means a mammal and includes humanand animal subjects, such as domestic animals (e.g., horses, dogs, cats,etc.). The terms “subject” and “patient” are used interchangeably. Insome embodiments, the “patient” or “subject” means an animal, preferablya mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. The amount of compounds of the presentinvention that may be combined with the carrier materials to produce acomposition in a single dosage form will vary depending upon the hosttreated, the particular mode of administration, etc. Preferably,provided compositions are formulated so that a dosage of between 0.01 toabout 100 mg/kg, or about 0.1 mg/kg to about 50 mg/kg, and preferablyfrom about 1 mg/kg to about 25 mg/kg, of subject body weight/day of theinhibitor can be administered to a patient receiving these compositionsto obtain the desired therapeutic effect. The amount of a compound ofthe present invention in the composition will also depend upon theparticular compound in the composition.

The expression “unit dosage form” as used herein refers to a physicallydiscrete unit of a provided compound and/or compositions thereofappropriate for the subject to be treated. It will be understood,however, that the total daily usage of the active agent (i.e., compoundsand compositions of the present invention) will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular subject (i.e., patient)or organism will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; activity of specificactive agent employed; specific composition employed; age, body weight,general health, sex and diet of the subject; time of administration,route of administration, and rate of excretion of the specific activeagent employed; duration of the treatment, and like factors well knownin the medical arts.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques.

As used herein, a “therapeutically effective amount” means an amount ofa substance (e.g., a therapeutic agent, composition, and/or formulation)that elicits a desired biological response. In some embodiments, atherapeutically effective amount of a substance is an amount that issufficient, when administered as part of a dosing regimen to a subjectsuffering from or susceptible to a disease, disorder, and/or condition,to treat, diagnose, prevent, and/or delay the onset of the disease,disorder, and/or condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of a substance may varydepending on such factors as the desired biological endpoint, thesubstance to be delivered, the target cell or tissue, etc. For example,the effective amount of a provided compound in a formulation to treat adisease, disorder, and/or condition is the amount that alleviates,ameliorates, relieves, inhibits, prevents, delays onset of, reducesseverity of and/or reduces incidence of one or more symptoms or featuresof the disease, disorder, and/or condition. In some embodiments, a“therapeutically effective amount” is at least a minimal amount of aprovided compound, or composition containing a provided compound, whichis sufficient for treating one or more symptoms of an MK2-mediateddisease or disorder.

As used herein, the terms “treatment,” “treat,” and “treating” refer topartially or completely alleviating, inhibiting, delaying onset of,preventing, ameliorating and/or relieving a disorder or condition, orone or more symptoms of the disorder or condition, as described herein.In some embodiments, treatment may be administered after one or moresymptoms have developed. In some embodiments, the term “treating”includes preventing or halting the progression of a disease or disorder.In other embodiments, treatment may be administered in the absence ofsymptoms. For example, treatment may be administered to a susceptibleindividual prior to the onset of symptoms (e.g., in light of a historyof symptoms and/or in light of genetic or other susceptibility factors).Treatment may also be continued after symptoms have resolved, forexample to prevent or delay their recurrence. Thus, in some embodiments,the term “treating” includes preventing relapse or recurrence of adisease or disorder.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits the target protein kinase, MK2, with measurableaffinity. In certain embodiments, an inhibitor has an IC₅₀ and/orbinding constant of less than about 50 μM, less than about 1 μM, lessthan about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in MK2 activity between a samplecomprising a compound of the present invention, or composition thereof,and MK2, and an equivalent sample comprising MK2, in the absence of saidcompound, or composition thereof.

As used herein, the term “irreversible” or “irreversible inhibitor”refers to an inhibitor (i.e. a compound) that is able to be covalentlybonded to a kinase in a substantially non-reversible manner. That is,whereas a reversible inhibitor is able to bind to (but is generallyunable to form a covalent bond with) a kinase, and therefore can becomedissociated from the kinase, an irreversible inhibitor will remainsubstantially bound to a kinase once covalent bond formation hasoccurred. Irreversible inhibitors usually display time dependency,whereby the degree of inhibition increases with the time with which theinhibitor is in contact with the enzyme. In certain embodiments, anirreversible inhibitor will remain substantially bound to a kinase oncecovalent bond formation has occurred and will remain bound for a timeperiod that is longer than the life of the protein.

Methods for identifying if a compound is acting as an irreversibleinhibitor are known to one of ordinary skill in the art. Such methodsinclude, but are not limited to, enzyme kinetic analysis of theinhibition profile of the compound with a kinase, the use of massspectrometry of the protein drug target modified in the presence of theinhibitor compound, discontinuous exposure, also known as “washout,”experiments, and the use of labeling, such as radiolabelled inhibitor,to show covalent modification of the enzyme, as well as other methodsknown to one of skill in the art.

As used herein, the term “drug resistance” refers to changes in thewild-type nucleic acid sequence coding a target protein, and/or theamino acid sequence of the target protein, and/or the amino acidsequence of another protein, which changes decrease or abolish theinhibitory effect of the inhibitor on the target protein. Withoutwishing to be bound by any particular theory, it is believed thatcertain compounds of the present invention, i.e., compounds that areirreversible kinase inhibitors, may be effective inhibitors of drugresistant forms of protein kinases.

3. Description of Exemplary Embodiments:

As described herein, the present invention provides irreversibleinhibitors of MK2 kinase. Without wishing to be bound by any particulartheory, it is believed that compounds of the invention comprise a moietycapable of covalently binding to a key cysteine residue in the bindingdomain of MK2 kinase. Such a moiety is referred to herein as a “reactivemoiety.” One of ordinary skill in the art will appreciate that MK2kinase, and mutants thereof, have a cysteine residue in the bindingdomain. Without wishing to be bound by any particular theory, it isbelieved that proximity of a reactive moiety, present on a provided MK2inhibitor, to the cysteine of interest facilitates covalent modificationof that cysteine by the reactive moiety.

The cysteine residues of interest can also be described by anidentifying portion of the amino acid sequence of MK2 kinase whichincludes the cysteine of interest. Thus, in certain embodiments, Cys140of MK2 is characterized in that Cys140 is the cysteine embedded in thefollowing amino acid sequence of MK2:

SEQ ID NO. 1: MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLIVME C LDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSALATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH.

For the purpose of clarity, Cys140 is provided in the abbreviated aminoacid sequence below:

SEQ ID NO. 2: NLYAGRKCLLIVIME C(140)LDGGELFSRIQDR.

In both SEQ ID NOS. 1 and 2, Cysteine 140 is highlighted in bold withunderlining.

In some embodiments, compounds of the present invention include areactive moiety characterized in that provided compounds covalentlymodify Cys140 of MK2.

In certain embodiments, compounds of the present invention include areactive moiety characterized in that a compound covalently modifies atarget of Cys140 of MK2, thereby irreversibly inhibiting the kinase.

Thus, in some embodiments, a reactive moiety present on a provided MK2inhibitor compound is capable of covalently binding to a cysteineresidue thereby irreversibly inhibiting the enzyme. In some embodiments,the cysteine residue is Cys140 of MK2. One of ordinary skill in the artwill recognize that a variety of reactive moieties, as defined herein,are suitable for such covalent bonding. Such reactive moieties include,but are not limited to, those described herein and depicted infra.

According to one aspect, the present invention provides a compound offormula I,

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ring A is phenyl or a 5-6 membered heteroaryl ring having 1-3        nitrogens;    -   T is a bivalent moiety selected from —N(R)—, —O—, —S—, —S(O)—,        —SO₂—, —C(S)—, —Si(R⁴)₂—, —P(R⁵)—, —P(O)₂—, or a bivalent        saturated straight or branched 1-3 membered hydrocarbon chain,        wherein the hydrocarbon chain is optionally substituted with oxo        or —OR;    -   each R is independently hydrogen or an optionally substituted        C₁₋₆ aliphatic, or:        -   two R groups on the same nitrogen are taken together with            the nitrogen to form a 3-7 membered saturated or partially            unsaturated heterocyclic ring having 1-3 heteroatoms            selected from nitrogen, oxygen, or sulfur;    -   R^(a) is hydrogen or an optionally substituted C₁₋₆ aliphatic;    -   R¹ is —R or —(CH₂)_(p)R^(x);    -   p is 0, 1, 2, or 3;    -   R^(x) is —CN, —NO₂, halogen, —OR, —SR, —N(R)₂, —C(O)N(R)₂,        —C(O)OR, —C(O)R, —N(R)C(O)R, —SO₂N(R)₂, or —N(R)SO₂;    -   R² is halogen, —CN, —SR^(y), —S(O)R^(y), —SO₂R^(y), —OSO₂R^(y),        —OC(O)R^(y), or —OP(O)₂OR^(y);    -   each R^(y) is independently selected from optionally substituted        C₁₋₆ aliphatic or optionally substituted phenyl;    -   R³ is hydrogen, optionally substituted C₁₋₆ aliphatic, —CN,        —NO₂, halogen, —OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy,        —C(O)N(R)-Cy, —C(O)-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy,        —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy, —(CH₂)_(n)—N(R)-Cy, or        —(CH₂)_(m)-Cy;    -   each R⁴ is independently hydrogen, —OR, C₁₋₆ aliphatic, phenyl,        or a 5-6 membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   each R⁵ is independently —OR, C₁₋₆ aliphatic, phenyl, or a 5-6        membered heteroaryl ring having 1-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;    -   each of m and n is independently 0-4; and    -   each Cy is independently an optionally substituted ring selected        from a 3-9 membered saturated or partially unsaturated        monocyclic carbocyclic ring, a 3-9 membered saturated or        partially unsaturated monocyclic heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, phenyl, a 5-6 membered heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, a 7-12 membered saturated or partially unsaturated fused        or bridged bicyclic carbocyclic ring, or a 7-12 membered        saturated or partially unsaturated fused or bridged bicyclic        heterocyclic ring having 1-3 heteroatoms independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, the present invention provides a compound offormula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ring A is phenyl or a 5-6 membered heteroaryl ring having 1-3        nitrogens; or an 8-14 membered bicyclic heteroaryl ring having        1-4 heteroatoms independently selected from nitrogen, oxygen,        and sulfur;    -   T is a bivalent moiety selected from —N(R)—, —O—, —S—, —S(O)—,        —SO₂—, —C(S)—, —Si(R⁴)₂—, —P(R⁵)—, —P(O)₂—, or a bivalent        saturated straight or branched 1-3 membered hydrocarbon chain,        wherein the hydrocarbon chain is optionally substituted with oxo        or —OR;    -   each R is independently hydrogen or an optionally substituted        C₁₋₆ aliphatic, or:        -   two R groups on the same nitrogen are taken together with            the nitrogen to form a 3-7 membered saturated or partially            unsaturated heterocyclic ring having 1-3 heteroatoms            selected from nitrogen, oxygen, or sulfur;    -   R^(a) is hydrogen or an optionally substituted C₁₋₆ aliphatic;    -   R¹ is —R or —(CH₂)_(p)R^(x);    -   p is 0, 1, 2, or 3;    -   R^(x) is —CN, —NO₂, halogen, —OR, —SR, —N(R)₂, —C(O)N(R)₂,        —C(O)OR, —C(O)R, —N(R)C(O)R, —SO₂N(R)₂, or —N(R)SO₂;    -   R² is halogen, —CN, —SR^(y), —S(O)R^(y), —SO₂R^(y), —OSO₂R^(y),        —OC(O)R^(y), or —OP(O)₂OR^(y);    -   each R^(y) is independently selected from optionally substituted        C₁₋₆ aliphatic or optionally substituted phenyl;    -   R³ is hydrogen, optionally substituted C₁₋₆ aliphatic, —CN,        —NO₂, halogen, —OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy,        —C(O)N(R)-Cy, —C(O)-Cy, O-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy,        —(CH₂)_(m)N(R)₂, —(CH₂)_(m)OR, —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy,        —(CH₂)_(n)—N(R)-Cy, or —(CH₂)_(m)-Cy;    -   each R⁴ is independently hydrogen, —OR, C₁₋₆ aliphatic, phenyl,        or a 5-6 membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   each R⁵ is independently —OR, C₁₋₆ aliphatic, phenyl, or a 5-6        membered heteroaryl ring having 1-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;    -   each of m and n is independently 0-4; and    -   each Cy is independently an optionally substituted ring selected        from a 3-9 membered saturated or partially unsaturated        monocyclic carbocyclic ring, a 3-9 membered saturated or        partially unsaturated monocyclic heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, phenyl, a 5-6 membered heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, a 7-12 membered saturated or partially unsaturated fused        or bridged bicyclic carbocyclic ring, or a 7-12 membered        saturated or partially unsaturated fused or bridged bicyclic        heterocyclic ring having 1-3 heteroatoms independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, the present invention provides a compound offormula I wherein said compound is other than:

In some embodiments, the present invention provides a compound offormula I′ wherein said compound is other than:

As defined generally above and discussed throughout, each R^(∘) isindependently hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6membered heteroaryl ring), or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; wherein R^(∘) may be substituted byhalogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●); or two independent occurrences ofR^(∘) may be optionally taken together with their intervening atom(s),form a 3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some such embodiments, each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

As defined generally above, T is a bivalent moiety selected from —N(R)—,—O—, —S—, —S(O)—, —SO₂—, —C(S)—, —Si(R⁴)₂—, —P(R⁵)—, —P(O)₂—, or abivalent saturated straight or branched 1-3 membered hydrocarbon chain,wherein the hydrocarbon chain is optionally substituted with oxo or —OR,wherein each R is independently hydrogen or an optionally substitutedC₁₋₆ aliphatic. In some embodiments, T is —N(R)—, —O—, or —S—. In someembodiments, T is —NH—. In other embodiments, T is —O—. In otherembodiments, T is —S—. In some embodiments, T is —N(R)— wherein R isoptionally substituted C₁₋₆ aliphatic. In some embodiments, T is—N(CH₃)—. In some embodiments, T is —N(R)— wherein R is C₁₋₆ aliphaticoptionally substituted with —(CH₂)₀₋₄N(R^(∘))₂ or —(CH₂)₀₋₄OR^(∘). Insome such embodiments, R^(∘) is as defined above and described herein.In some embodiments, T is —N(R)— wherein R is C₁₋₆ aliphatic optionallysubstituted with —(CH₂)₀₋₄N(R^(∘))₂ or —(CH₂)₀₋₄OR^(∘), wherein R^(∘) ishydrogen or C₁₋₆ aliphatic. In some embodiments, T is—N(CH₂CH₂N(R^(∘))₂)— or —N(CH₂CH₂OR^(∘))—, wherein R^(∘) is hydrogen orC₁₋₆ aliphatic. In certain embodiments, T is selected from the Tmoieties present on the compounds depicted in Table 1, below.

In some embodiments, T is a bivalent moiety selected from —N(R)—, —O—,—S—, —S(O)—, —SO₂—, —C(S)—, —Si(R⁴)₂—, —P(R⁵)—, —P(O)₂—, a bivalent 3-7membered cycloalkylene, or a bivalent saturated straight or branched 1-3membered hydrocarbon chain, wherein the hydrocarbon chain is optionallysubstituted with halogen, —R, deuterium, oxo, or —OR, wherein each R isindependently hydrogen or an optionally substituted C₁₋₆ aliphatic. Insome embodiments, T is a bivalent 3-7 membered cycloalkylene, or abivalent saturated straight or branched 1-3 membered hydrocarbon chain,wherein the hydrocarbon chain is optionally substituted with halogen,—R, deuterium, oxo, or —OR, wherein each R is independently hydrogen oran optionally substituted C₁₋₆ aliphatic. In some embodiments, T is abivalent 3-7 membered cycloalkylene. In some embodiments, T iscyclopropylene. In some embodiments, T is 1,1-cyclopropylene. In someembodiments, T is a bivalent saturated straight or branched 1-3 memberedhydrocarbon chain, wherein the hydrocarbon chain is optionallysubstituted with halogen, —R, deuterium, oxo, or —OR, wherein each R isindependently hydrogen or an optionally substituted C₁₋₆ aliiphatic. Insome embodiments, T is —CF₂—, —C(Me)₂-, or —CD₂-.

As defined generally above, R^(a) is hydrogen or an optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R^(a) is hydrogen. Insome embodiments, R^(a) is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R^(a) is methyl.

As defined generally above, R¹ is —R or —(CH₂)_(p)R^(x), wherein p is 0,1, 2, or 3, and R^(x) is —CN, —NO₂, halogen, —OR, —SR, —N(R)₂,—C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)C(O)R, —SO₂N(R)₂, or —N(R)SO₂. Incertain embodiments, R¹ is —R, —CH₂OR, or —CH₂N(R)₂.

In some embodiments, R¹ is —R, wherein —R is optionally substituted C₁₋₆aliphatic. In some embodiments, R¹ is methyl. In some embodiments, R¹ is—CH₂R^(x), wherein R^(x) is —OR or —N(R)₂. In certain embodiments, R is—CH₂OCH₃. In some embodiments, R¹ is —CH₂NH₂. In some embodiments, R¹ is—CH₂NHCH₃. In some embodiments, R¹ is —CH₂N(CH₃)₂. In certainembodiments, R¹ is —CH₂OH. In certain embodiments, R¹ is selected fromthe R¹ moieties present on the compounds depicted in Table 1, below.

As defined generally above, Ring A is phenyl or a 5-6 memberedheteroaryl ring having 1-3 nitrogens. In some embodiments, Ring A isphenyl or a 5-6 membered monocyclic heteroaryl ring having 1-3nitrogens, or a 8-14 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring A is phenyl. In some embodiments, Ring A is a 5-6membered heteroaryl ring having 1-3 nitrogens. In some embodiments, RingA is a 8-14 bicyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, Ring A is phenyl and R is an electronwithdrawing group. One of ordinary skill in the art would recognize thatcertain moieties encompassed by the definition of R³ are electronwithdrawing groups. Thus, in some embodiments, Ring A is phenyl and R³is selected from —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR, -Cy,—C(O)N(R)-Cy, or —C(O)—Cy. In some embodiments, Ring A is phenyl and R³is selected from —CN, halogen, —C(O)N(R)₂, —C(O)OR, -Cy, —C(O)N(R)-Cy,or —C(O)—Cy. In certain embodiments, Ring A is phenyl and R³ ishydrogen, optionally substituted C₁₋₆ aliphatic, —CN, —NO₂, halogen,—OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy, —C(O)N(R)-Cy, —C(O)—Cy, —O-Cy,—O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy. —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy,—(CH₂)_(n)—N(R)-Cy, or —(CH₂)_(m)-Cy. In certain embodiments, Ring A isphenyl and R³ is hydrogen, optionally substituted C₁₋₆ aliiphatic, —CN,halogen, —OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy, —C(O)N(R)-Cy, —C(O)—Cy,—O-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy, —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy,—(CH₂)_(n)—N(R)-Cy, or —(CH₂)_(m)—Cy. In certain embodiments, Ring A isphenyl and R³ is selected from —CN, —NO₂, or halogen. In certainembodiments, Ring A is phenyl and R³ is selected from —CN or halogen.

In some embodiments, Ring A is phenyl and R² is at a meta position ofthe phenyl ring and R³ is at an ortho position of the phenyl ring. Insome embodiments, Ring A is:

wherein R² is as defined above and herein and R³ is an electronwithdrawing group and wherein the wavy line indicates the point ofattachment of Ring A to T.

In some embodiments, Ring A is:

wherein R² is halogen and R³ is —CN and wherein the wavy line indicatesthe point of attachment of Ring A to T.

In some embodiments, Ring A is

wherein the wavy line indicates the point of attachment of Ring A to T.

In some embodiments, Ring A is a 5-6-membered heteroaryl ring having 1-3nitrogens. In some embodiments, Ring A is a 5-membered heteroaryl ringhaving 1-3 nitrogens. In some embodiments, Ring A is a 6-memberedheteroaryl ring having 1-3 nitrogens. In some embodiments, Ring A ispyridyl. In some embodiments, Ring A is pyrimidinyl. In someembodiments, Ring A is pyridazinyl. In some embodiments, Ring A ispyrazinyl. In some embodiments Ring A is triazinyl.

In some embodiments, Ring A is a 8-14 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, Ring A is a 9-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 9-10membered bicyclic heteroaryl ring having 2-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Ais selected from:

As defined generally above, R² is halogen, —CN, —SR^(y), —S(O)R^(y),—SO₂R, —OSO₂R^(y), —OC(O)R^(y), or —OP(O)₂OR, wherein each R^(y) isindependently selected from optionally substituted C₁₋₆ aliphatic oroptionally substituted phenyl. One of ordinary skill in the art willrecognize that moieties encompassed by the definition of R² are leavinggroups. Leaving groups are well known in the art, e.g., see, “AdvancedOrganic Chemistry,” Jerry March, 4^(th) Ed., pp. 351-357, John Wiley andSons, N.Y. (1992). In some embodiments, R² is halogen. In someembodiments, R² is fluoro. In certain embodiments, R² is chloro. In someembodiments, R² is —SR^(y) or —SO₂R^(y). In some embodiments, R² is—SR^(y) or —SO₂R^(y) and R^(y) is optionally substituted C₁₋₆ aliphatic.In some embodiments, R² is —SCH₃ or —SO₂CH₃. In some embodiments, R² isselected from the R² moieties present on the compounds depicted in Table1, below.

As defined generally above, R³ is hydrogen, optionally substituted C₁₋₆aliphatic, —CN, —NO₂, halogen, —OR, —N(R)₂, —C(O)N(R)₂, —C(O)OR, -Cy,—C(O)N(R)-Cy, —C(O)—Cy, —O-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy,—N(R)—Cy, —N(R)—(CH₂)_(n)-Cy, —(CH₂)_(n)—N(R)-Cy, or —(CH₂)_(m)-Cywherein each n is independently 0, 1, 2, 3, or 4, and each Cy isindependently an optionally substituted ring selected from a 3-9membered saturated or partially unsaturated carbocyclic ring or a 3-9membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur,phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, a 7-12membered saturated or partially unsaturated fused or bridged bicycliccarbocyclic ring, or a 7-12 membered saturated or partially unsaturatedfused or bridged bicyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Cy is an optionally substituted 3-9 memberedsaturated or partially unsaturated carbocyclic ring. In someembodiments, Cy is an optionally substituted 3-7 membered saturated orpartially unsaturated carbocyclic ring. In some embodiments, Cy is anoptionally substituted 3-7 membered saturated carbocyclic ring. In someembodiments, Cy is an optionally substituted cyclopropyl or cyclohexylring.

In some embodiments, Cy is an optionally substituted 3-9 memberedsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Cy is an optionally substituted 3-7 membered saturatedor partially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Cy is an optionally substituted 5-6 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Cy is an optionally substituted 4-6 memberedsaturated heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, Cy isan optionally substituted 4-membered saturated heterocyclic ring having1 heteroatom selected from nitrogen, oxygen, and sulfur. In someembodiments, Cy is an optionally substituted 5-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionallysubstituted 6-membered saturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, Cy is an optionally substituted group selected fromoxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, and morpholinyl.

In some embodiments, Cy is an optionally substituted 3-7 memberedpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In some suchembodiments, Cy is 3,6-dihydro-2H-pyranyl or1,2,3,6-tetrahydropyridinyl.

In some embodiments, Cy is optionally substituted phenyl.

In some embodiments, Cy is an optionally substituted 5-6 memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Cy is optionallysubstituted pyridyl.

In some embodiments, Cy is an optionally substituted 7-12 memberedsaturated or partially unsaturated fused or bridged bicyclic carbocyclicring.

In some embodiments, Cy is an optionally substituted 7-12 memberedsaturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionallysubstituted 8-membered saturated bridged bicyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some such embodiments, Cy is(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octyl (i.e., a moiety having thestructure

In some embodiments, a substitutable carbon atom of Cy is optionallysubstituted with halogen, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘),—(CH₂)₀₋₄N(R^(∘))₂, wherein:

-   -   R^(∘) is hydrogen or C₁₋₆ aliphatic optionally substituted with        halogen or —(CH₂)₀₋₂OR^(●), and    -   R* is C₁₋₄ aliphatic; or:        -   two independent occurrences of R^(∘), taken together with            their intervening atom(s), form a 3-6 membered ring            saturated ring having 0-1 heteroatoms selected from            nitrogen, oxygen or sulfur.

In some embodiments, a substitutable nitrogen atom of Cy is optionallysubstituted with —(CH₂)₀₋₄R^(†), wherein R^(†) is hydrogen or C₁₋₆aliphatic.

In some embodiments, Cy is

wherein each R^(∘) is C₁₋₆ aliphatic. In some embodiments, Cy is

wherein each R^(∘) is C₁₋₆ aliphatic and the two occurrences of R^(∘),taken together with their intervening atom(s), form a 3-4 membered ringsaturated ring having 0-1 heteroatoms selected from nitrogen, oxygen orsulfur. In some such embodiments, Cy is 3-azabicyclo[3.1.0]hexyl (i.e.,a moiety having the structure

In some embodiments, Cy is

wherein each R^(∘) is C₁₋₆ aliiphatic and the two occurrences of R^(∘),taken together with their intervening atom(s), form a 3-4 membered ringsaturated ring having 0-1 heteroatoms selected from nitrogen, oxygen orsulfur. In some such embodiments, Cy is 3-azabicyclo[3.1.1]heptyl (i.e.,a moiety having the structure

In certain embodiments, Cy is selected from:

One of ordinary skill in the art would recognize that the definition ofR³ includes electron-withdrawing groups (e.g., —CN, —NO₂, halogen, etc.)and solubilizing groups (e.g., —N(R)₂, -Cy, —C(O)N(R)-Cy, —C(O)—Cy,—O-Cy, —O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy, —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy,—(CH₂)_(n)—N(R)-Cy, —(CH₂)_(m)-Cy, etc.). Thus, in some embodiments,R^(●) is an electron-withdrawing group. In other embodiments, R³ is asolubilizing group.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isoptionally substituted C₁₋₆ aliphatic, —CN, —NO₂, halogen, —OR, —N(R)₂,—C(O)N(R)₂, —C(O)OR, -Cy, —C(O)N(R)-Cy, —C(O)—Cy, —O-Cy,—O—(CH₂)_(n)-Cy, —(CH₂)_(n)—O-Cy, —N(R)—Cy, —N(R)—(CH₂)_(n)-Cy,—(CH₂)_(n)—N(R)-Cy, or —(CH₂)_(m)-Cy. In some embodiments, R³ isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R³ is—(CH₂)_(n)—O-Cy, —(CH₂)_(m)—Cy, —(CH₂)₀₋₄N(R^(∘))₂, or —(CH₂)₀₋₄OR^(∘).In some embodiments, R³ is C₁₋₆ aliphatic optionally substituted with—(CH₂)₀₋₄N(R^(∘))₂. In some such embodiments, R^(∘) is hydrogen oroptionally substituted C₁₋₆ aliphatic. In some embodiments, R³ is C₁₋₆aliphatic optionally substituted with —(CH₂)₀₋₄SO₂R^(∘), —(CH₂)₀₋₄OR^(∘)or —(CH₂)₀₋₄N(R^(∘))₂, wherein R^(∘) is hydrogen or optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R³ is —(CH₂)₀₋₄OR^(∘).In some embodiments, R³ is —(CH₂)₀₋₄SO₂R^(∘). In some embodiments, R³ is—(CH₂)₀₋₄N(R^(∘))₂. In some embodiments, R³ is —(CH₂)₁₋₄N(R^(∘))₂. Insome embodiments, R³ is —CH₂N(R^(∘))₂. In some embodiments, R³ is—CH₂N(R^(∘))₂, —CH₂OR^(∘) or —CH₂SO₂R^(∘). In some such embodiments,R^(∘) is C₁₋₆ aliphatic optionally substituted with —CN, halogen or—(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄ aliphatic. In some embodiments,R³ is —CH₂OH, —CH₂OCH₃, —CH₂OCHF₂, —CH₂OCH₂CHF₂, —CH₂OCH₂CH₃,—CH₂OCD₂CD₃, —CH₂OCH₂CH₂F, —CH₂OCH₂CH₂CN, —CH₂OC(CH₃)₃, —CH₂SO₂CH₃,—CH₂NHC(CH₃)₃, —CH₂N(CH₃)C(CH₃)₃, —CH₂N(CH₃)CH(CH₃)₂,—CH₂N(CH₂CH(CH₃)₂)₂, —CH₂N(CH₃)CH₂CH₂OCH₃, or —CH₂N(CH₃)CH₂CH₂OCH₂CH₃.

In some embodiments, R³ is —(CH₂)_(m)-Cy, wherein Cy is defined as aboveand described herein.

In some embodiments, R³ is —CH₂Cy, wherein Cy is an optionallysubstituted 5-6 membered saturated or partially unsaturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R³ is —(CH₂)_(m)-Cy, wherein Cy is an optionallysubstituted 7-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is -Cy. In some embodiments, R³ is -Cy, whereinCy is an optionally substituted 5-6 membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R³ is -Cy, wherein Cy is an optionally substituted7-12 membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R³ is-Cy, wherein Cy is as defined above and described herein.

In some embodiments, R³ is optionally substituted C₁₋₆ aliphaticselected from —CH₂OH, —CH₂OCH₃ and —CH₃.

In some embodiments, R³ is —OR, wherein R is optionally substituted C₁₋₆aliiphatic. In some embodiments, R³ is selected from —O(CH₂)₂OCH₃,—O(CH)₂N(CH₃)₂, and —OCH₃.

In some embodiments, R³ is —N(R)₂, wherein R is optionally substitutedC₁₋₆ aliphatic. In some embodiments, R³ is —N(CH₃)₂.

In certain embodiments, R³ is halogen, —CN, NO₂, —C(O)N(R)₂, or —C(O)OR.In some embodiments, R³ is halogen, —CN, or NO₂. In some embodiments, R³is fluoro, chloro or bromo. In certain embodiments, R³ is —C(O)N(R)₂ or—C(O)OR, wherein each R is as defined above and described herein. Incertain embodiments, R³ is selected from —C(O)NH₂, —C(O)OCH₂CH₃, and—OC(O)CH₃. In certain embodiments, R³ is selected from —C(O)NH₂,—C(O)OCH₃, —C(O)OCH₂CH₃, and —OC(O)CH₃.

In certain embodiments, R³ is -Cy, —(CH₂)_(m)-Cy, —C(O)N(R)-Cy,—C(O)—Cy, —OR, —O-Cy, or —O—(CH₂)_(n)Cy, wherein each of R, n, m, and-Cy is as defined above and described herein.

In some embodiments, R³ is -Cy, —(CH₂)_(m)-Cy, —C(O)N(R)-Cy, —C(O)—Cy,—O-Cy, or —O—(CH₂)_(n)-Cy, wherein each -Cy is independently anoptionally substituted ring selected from a 3-7 membered saturated orpartially unsaturated carbocyclic ring. In some embodiments, R³ is -Cy,—(CH₂)_(m)-Cy, —C(O)N(R)-Cy, —C(O)—Cy, —O-Cy, or —O—(CH₂)_(n)-Cy,wherein each -Cy is an optionally substituted cyclopropyl ring.

In some embodiments, R³ is -Cy, —(CH₂)_(m)-Cy, —C(O)N(R)-Cy, —C(O)—Cy,—O-Cy, or —O—(CH₂)_(n)-Cy, wherein each -Cy is independently anoptionally substituted ring selected from a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R³ is-Cy, —(CH₂)_(m)-Cy, —C(O)N(R)-Cy, —C(O)—Cy, —O-Cy, or—O—(CH₂)_(n)-Cy, wherein each -Cy is independently an optionallysubstituted ring selected from oxetanyl, piperidinyl, pyrrolidinyl,tetrahydrofuranyl, piperazinyl, and morpholinyl. In some embodiments, R³is -Cy, —(CH₂)_(m)-Cy, —C(O)N(R)-Cy, —C(O)—Cy, —O-Cy, or —O—(CH₂)_(n)Cy,wherein each -Cy is independently an optionally substituted ringselected from oxetanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperazinyl, and morpholinyl. In some embodiments, R³is —(CH₂)_(m)-Cy or C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄OR^(∘). Insome embodiments, R³ is —CH₂Cy or —CH₂OR^(∘). In some such embodiments,R^(∘) is as defined above and described herein. In some embodiments, R³is —(CH₂)_(m)-Cy or —(CH₂)_(m)OR. In some embodiments R³ is —CH₂Cy or—CH₂OR. In some embodiments R³ is —(CH₂)_(m)-Cy where Cy is optionallysubstituted piperidinyl.

As defined generally above, each of m and n is independently 0-4. Insome embodiments, m is 1-2. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, n is 1-2. In some embodiments,n is 1. In some embodiments, n is 2.

In some embodiments, R³ is selected from the R³ moieties present on thecompounds depicted in Table 1, below.

In some embodiments, the present invention provides a compound of anyone of formulas II, III, IV, V, or VI:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, T,R², and R³ is as defined above and described herein.

In some embodiments, the present invention provides a compound of anyone of formulas VII, VIII, IX, X, XI, or XII:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, T,R², R, and -Cy is as defined above and described herein.

In some embodiments, the present invention provides a compound of anyone of formulas XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, T,R², R, R^(∘), and -Cy is as defined above and described herein.

In some embodiments, the present invention provides a compound of anyone of formulas XXV or XXVI:

In certain embodiments, the present invention provides a compound of anyone of formulas I through VI. In certain embodiments, the presentinvention provides a compound of any one of formulas VII through XIV. Incertain embodiments, the present invention provides a compound of anyone of formulas II, III, or IV. In certain embodiments, the presentinvention provides a compound of any one of formulas II, III, or V. Incertain embodiments, the present invention provides a compound of anyone of formulas II, IV, or V. In certain embodiments, the presentinvention provides a compound of any one of formulas III, IV, or V. Incertain embodiments, the present invention provides a compound of anyone of formulas III, IV, or VI. In certain embodiments, the presentinvention provides a compound of any one of formulas III, V, or VI. Incertain embodiments, the present invention provides a compound of anyone of formulas VII, VIII, IX, X, XII, XIII, or XIV. In certainembodiments, the present invention provides a compound of any one offormulas VII, VIII, IX, XII, XIII, or XIV. In certain embodiments, thepresent invention provides a compound of any one of formulas VII, IX,XII, XIII, or XIV. In certain embodiments, the present inventionprovides a compound of any one of formulas VIII, X, XI, or XIII. Incertain embodiments, the present invention provides a compound of anyone of formulas XX or XXI. In certain embodiments, the present inventionprovides a compound of any of formulas XVII or XVIII. In certainembodiments, the present invention provides a compound of any one offormulas XXV or XXVI.

In certain embodiments, the present invention provides a compound of anyone of formulas I through XXVI wherein T is —O—. In certain embodiments,the present invention provides a compound of any one of formulas Ithrough XIV wherein T is —O—. In certain embodiments, the presentinvention provides a compound of any one of formulas I through VIwherein T is —O—. In certain embodiments, the present invention providesa compound of any one of formulas VII through XIV wherein T is —O—. Incertain embodiments, the present invention provides a compound of anyone of formulas II, III, or IV wherein T is —O—. In certain embodiments,the present invention provides a compound of any one of formulas II,III, or V wherein T is —O—. In certain embodiments, the presentinvention provides a compound of any one of formulas II, IV, or Vwherein T is —O—. In certain embodiments, the present invention providesa compound of any one of formulas III, IV, or V wherein T is —O—. Incertain embodiments, the present invention provides a compound of anyone of formulas III, IV, or VI wherein T is —O—. In certain embodiments,the present invention provides a compound of any one of formulas III, V,or VI wherein T is —O—. In certain embodiments, the present inventionprovides a compound of any one of formulas VI, VIII, IX, X, XII, XIII,or XIV wherein T is —O—. In certain embodiments, the present inventionprovides a compound of any one of formulas VII, VIII, IX, XII, XIII, orXIV wherein T is —O—. In certain embodiments, the present inventionprovides a compound of any one of formulas VII, IX, XII, XIII, or XIVwherein T is —O—. In certain embodiments, the present invention providesa compound of any one of formulas VIII, X, XI, or XIII wherein T is —O—.

In certain embodiments, the present invention provides a compound of anyone of formulas I through XXVI wherein T is —NH—. In certainembodiments, the present invention provides a compound of any one offormulas I through XIV wherein T is —NH—. In certain embodiments, thepresent invention provides a compound of any one of formulas I throughVI wherein T is —NH—. In certain embodiments, the present inventionprovides a compound of any one of formulas VII through XIV wherein T is—NH—. In certain embodiments, the present invention provides a compoundof any one of formulas i, III, or IV wherein T is —NH—. In certainembodiments, the present invention provides a compound of any one offormulas II, III, or V wherein T is —NH—. In certain embodiments, thepresent invention provides a compound of any one of formulas II, IV, orV wherein T is —NH—. In certain embodiments, the present inventionprovides a compound of any one of formulas II, IV, or V wherein T is—NH—. In certain embodiments, the present invention provides a compoundof any one of formulas III, IV, or VI wherein T is —NH—. In certainembodiments, the present invention provides a compound of any one offormulas III, V, or VI wherein T is —NH—. In certain embodiments, thepresent invention provides a compound of any one of formulas VII, VIII,IX, X, XII, XIII, or XIV wherein T is —NH—. In certain embodiments, thepresent invention provides a compound of any one of formulas VII, VIII,IX, XII, XIII, or XIV wherein T is —NH—. In certain embodiments, thepresent invention provides a compound of any one of formulas VII, IX,XII, XIII, or XIV wherein T is —NH—. In certain embodiments, the presentinvention provides a compound of any one of formulas VIII, X, XI, orXIII wherein T is —NH—.

In certain embodiments, the present invention provides a compound of anyone of formulas I through XXIV wherein R² is chloro or fluoro. Incertain embodiments, the present invention provides a compound of anyone of formulas I through XIV wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas I through VI wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas VII through XIV wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas II, III, or IV wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas I, III, or V wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas III, IV, or V wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas III, IV, or V wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas III, IV, or VI wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas III, V, or VI wherein R² is chloro or fluoro. In certainembodiments, the present invention provides a compound of any one offormulas VII, VIII, IX, X, XII, XIII, or XIV wherein R² is chloro orfluoro. In certain embodiments, the present invention provides acompound of any one of formulas VII, VIII, IX, XII, XIII, or XIV whereinR² is chloro or fluoro. In certain embodiments, the present inventionprovides a compound of any one of formulas VII, IX, XII, XIII, or XIVwherein R² is chloro or fluoro. In certain embodiments, the presentinvention provides a compound of any one of formulas VIII, X, XI, orXIII wherein R² is chloro or fluoro.

In certain embodiments, the present invention provides a compound of oneof formulas I, I′, or III, wherein R² is halogen. In certainembodiments, the present invention provides a compound of one offormulas I or III, wherein R² is halogen. In certain embodiments, thepresent invention provides a compound of formula I′, wherein R² ishalogen.

In certain embodiments, the present invention provides a compound of oneof formulas I or III, wherein T is —O— and R² is halogen. In certainembodiments, the present invention provides a compound of one offormulas I or III, wherein T is —O—, R² is halogen, and R³ is —CH₂Cy. Incertain embodiments, the present invention provides a compound of one offormulas I or III, wherein T is —O—, R² is halogen, and R³ is—(CH₂)_(m)Cy, —(CH₂)_(n)OCy, or C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄N(R^(∘))₂, or —(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘)is as defined above and described herein.

In certain embodiments, the present invention provides a compound offormula I′, wherein T is —O— and R² is halogen. In certain embodiments,the present invention provides a compound of formula I′, wherein T is—O—, R² is halogen, and R³ is —CH₂Cy. In certain embodiments, thepresent invention provides a compound of one of formula I′ wherein T is—O—, R² is halogen, and R³ is —(CH₂)_(m)Cy, —(CH₂)_(m)OCy,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR.

In certain embodiments, the present invention provides a compound of oneof formulas I or II wherein R³ is —(CH₂)_(m)Cy, —(CH₂)_(n)OCy, or C₁₋₆aliiphatic substituted by —(CH₂)₀₋₄N(R^(∘))₂, or —(CH₂)₀₋₄OR^(∘). Insome such embodiments, R^(∘) is as defined above and described herein.In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is —(CH₂)_(m)Cy, or —(CH₂)_(n)OCy. Insome embodiments the present invention provides a compound of one offormulas I or III wherein R³ is C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄N(R^(∘))₂, or —(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘)is as defined above and described herein. In certain embodiments, thepresent invention provides a compound of one of formulas I or IIIwherein R³ is C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄N(R^(∘))₂, or—(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen, C₁₋₆ aliphatic, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R^(∘) is optionally substituted by halogen, —CN or—(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄ aliphatic. In certainembodiments, the present invention provides a compound of one offormulas I or II wherein R³ is —(CH₂)_(m)Cy or C₁₋₆ aliphaticsubstituted by —(CH₂)₀₋₄R^(∘). In some such embodiments, R^(∘) is asdefined above and described herein. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—(CH₂)_(m)Cy or C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄OR^(∘), whereinR^(∘) is hydrogen, C₁₋₆ aliiphatic, or a 5-6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R^(∘) is optionallysubstituted by halogen, —CN or —(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄aliphatic. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is —(CH₂)_(m)Cy. Incertain embodiments, the present invention provides a compound of one offormulas I or II wherein R³ is —(CH₂)_(n)OCy. In some embodiments thepresent invention provides a compound of one of formulas I or II whereinR³ is C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄N(R^(∘))₂. In some suchembodiments, R^(∘) is as defined above and described herein. In someembodiments, the present invention provides a compound of one offormulas I or III wherein R³ is C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄N(R^(∘))₂, wherein R^(∘) is hydrogen, C₁₋₆ aliphatic, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R^(∘) is optionally substituted by —(CH₂)₀₋₂OR^(●), whereinR^(●) is C₁₋₄ aliphatic. In some embodiments the present inventionprovides a compound of one of formulas I or HI wherein R³ is C₁₋₆aliphatic substituted by —(CH₂)₀₋₄OR^(∘). In some such embodiments,R^(∘) is as defined above and described herein. In some embodiments thepresent invention provides a compound of one of formulas I or IIIwherein R³ is C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄OR^(∘), whereinR^(∘) is hydrogen, C₁₋₆ aliphatic, or a 5-6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R^(∘) is optionallysubstituted by halogen, —CN or —(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄aliphatic. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is —(CH₂)_(m)Cy,—(CH₂)_(n)OCy, or C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄N(R^(∘))₂, or—(CH₂)₀₋₄OR^(∘), wherein each R^(∘) is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, andR^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●). In some suchembodiments, R^(●) is C₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound of oneof formula I′ wherein R³ is —(CH₂)_(m)Cy, —(CH₂)_(n)OCy,—(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(m)Cy,or —(CH₂)_(n)OCy. In some embodiments the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)N(R^(∘))₂, or—(CH₂)_(m)OR. In certain embodiments, the present invention provides acompound of one of formula I′ wherein R³ is —(CH₂)_(m)Cy or—(CH₂)_(m)OR. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)Cy. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(n)OCy. In some embodiments the present inventionprovides a compound of formula I′ wherein R³ is —(CH₂)_(m)N(R)₂. In someembodiments the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(m)OR. In certain embodiments, the presentinvention provides a compound of one of formula I′ wherein R³ is—(CH₂)_(m)Cy, —(CH₂)_(n)OCy, —(CH₂)_(m)N(R)₂, or —(CH₂)_(m)OR, whereineach R is independently hydrogen or C₁₋₆ aliphatic, wherein saidaliphatic or said Cy may be substituted with halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR)R^(∘);—(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂;—OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is independently hydrogen,C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroarylring), or a 5-6-membered saturated, partially unsaturated, or aryl ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and R^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●),-(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂;—O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃,—C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SSR^(●). In some such embodiments, R^(●) is C₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is —(CH₂)_(m)Cy where Cy is anoptionally substituted 3-9 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturatedor partially unsaturated fused or bridged bicyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is —(CH₂)_(m)Cy where Cyis an optionally substituted 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —(CH₂)_(m)Cy where Cy is an optionallysubstituted 7-12 membered saturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—(CH₂)_(m)Cy where Cy is a 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein saidring is optionally substituted with oxo, halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is as defined above anddescribed herein. In certain embodiments, the present invention providesa compound of one of formulas I or III wherein R³ is (CH₂)_(m)Cy whereCy is an optionally substituted 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein: asubstitutable carbon atom on Cy is optionally substituted with halogen,—(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom onCy is optionally substituted with —R^(†), wherein R^(●) is hydrogen orC₁₋₆ aliphatic optionally substituted by halogen or —(CH₂)₀₋₂OR^(●),wherein R^(●) is C₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In somesuch embodiments, two independent occurrences of R^(∘) may be optionallytaken together with their intervening atom(s), form a 3-12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is —CH₂Cy where Cy is an optionallysubstituted 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partiallyunsaturated fused or bridged bicyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —CH₂Cy where Cy is an optionallysubstituted 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—CH₂Cy where Cy is an optionally substituted 7-12 membered saturated orpartially unsaturated fused or bridged bicyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is —CH₂Cy where Cy is a3-9 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein said ring is optionally substituted withoxo, halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘). In some such embodiments,R^(∘) is as defined above and described herein. In certain embodiments,the present invention provides a compound of one of formulas I or mwherein R³ is —CH₂Cy where Cy is an optionally substituted 3-9 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein: a substitutable carbon atom on Cy is optionallysubstituted with halogen, —(CH₂)₄R^(∘), or —(CH₂)₀₋₄OR^(∘), and asubstitutable nitrogen atom on Cy is optionally substituted with —R^(†),wherein R^(∘) is hydrogen or C₁₋₆ aliphatic optionally substituted byhalogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄ aliphatic, and R^(†)is C₁₋₆ aliphatic. In some such embodiments, two independent occurrencesof R^(∘) may be optionally taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, the presentinvention provides a compound of one of formulas I or II wherein R³ is—CH₂Cy where Cy is a 7-12 membered saturated or partially unsaturatedfused or bridged bicyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein saidring is optionally substituted with oxo, halogen, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄4OR^(∘). In some such embodiments, R^(∘) is as defined aboveand described herein. In certain embodiments, the present inventionprovides a compound of one of formulas I or III wherein R³ is —CH₂Cywhere Cy is a 7-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein: a substitutablecarbon atom on Cy is optionally substituted with halogen,—(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom onCy is optionally substituted with —R^(†), wherein R^(∘) is hydrogen orC₁₋₆ aliphatic optionally substituted by halogen or —(CH₂)₀₋₂OR^(●),wherein R^(●) is C₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In somesuch embodiments, two independent occurrences of R^(∘) may be optionallytaken together with their intervening atom(s), form a 3-12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is (CH₂)_(m)Cy where Cy is an optionallysubstituted 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or a 6-12 membered saturated or partiallyunsaturated fused or bridged bicyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(m)Cy where Cy is an optionallysubstituted 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(m)Cywhere Cy is an optionally substituted 6-12 membered saturated orpartially unsaturated fused or bridged bicyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)Cy where Cy is a 3-9membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein said ring is optionally substituted with oxo, halogen;(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is asdefined above and described herein. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(m)Cywhere Cy is a 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom on Cyis optionally substituted with halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR,and a substitutable nitrogen atom on Cy is optionally substituted with—R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphatic optionallysubstituted by halogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments, twoindependent occurrences of R^(∘) may be optionally taken together withtheir intervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —CH₂Cy where Cy is an optionally substituted 3-9 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 6-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is —CH₂Cywhere Cy is an optionally substituted 3-9 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —CH₂Cy where Cy is an optionally substituted6-12 membered saturated fused or bridged bicyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the present invention provides acompound of formula I′ wherein R′ is —CH₂Cy where Cy is a 3-9 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein said ring is optionally substituted with oxo, halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is asdefined above and described herein. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —CH₂Cy whereCy is a 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom on Cyis optionally substituted with halogen, —(CH₂)₀₋₂R^(●), or—(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom on Cy is optionallysubstituted with —R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphaticoptionally substituted by halogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) isC₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments,two independent occurrences of R^(∘) may be optionally taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —CH₂Cy where Cy is a 6-12 membered saturatedfused or bridged bicyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein saidring is optionally substituted with oxo, halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is as defined above anddescribed herein. In certain embodiments, the present invention providesa compound of formula I′ wherein R³ is —CH₂Cy where Cy is a 6-12membered saturated fused or bridged bicyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein: a substitutable carbon atom on Cy is optionallysubstituted with halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), and asubstitutable nitrogen atom on Cy is optionally substituted with —R^(†),wherein R^(∘) is hydrogen or C₁₋₆ aliphatic optionally substituted byhalogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) is C₁₋₄ aliphatic, and R^(†)is C₁₋₆ aliphatic. In some such embodiments, two independent occurrencesof R^(∘) may be optionally taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is —(CH₂)_(n)OCy where Cy is a 3-9membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 7-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments, thepresent invention provides a compound of one of formulas I or II whereinR³ is —(CH₂)_(n)OCy where Cy is a 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —(CH₂)_(n)OCy where Cy is a 7-12membered saturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—(CH₂)_(n)OCy where Cy is a 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, wherein saidring is optionally substituted with oxo, halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is as defined above anddescribed herein. In certain embodiments, the present invention providesa compound of one of formulas I or III wherein R³ is —(CH₂)_(n)OCy whereCy is a 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom on Cyis optionally substituted with halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom on Cy is optionallysubstituted with —R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphaticoptionally substituted by halogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) isC₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments,two independent occurrences of R^(∘) may be optionally taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —(CH₂)_(n)OCy where Cy is a 7-12membered saturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein said ring is optionallysubstituted with oxo, halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘). In somesuch embodiments, R^(∘) is as defined above and described herein. Incertain embodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —(CH₂)_(n)OCy where Cy is a 7-12membered saturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom on Cyis optionally substituted with halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom on Cy is optionallysubstituted with —R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphaticoptionally substituted by halogen or —CH₂)₀₋₂OR^(●), wherein R^(●) isC₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments,two independent occurrences of R^(∘) may be optionally taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 3-9 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or a 6-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—(CH₂)_(n)OCy where Cy is a 3-9 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(n)OCy where Cy is a 6-12 membered saturated orpartially unsaturated fused or bridged bicyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 3-9membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 6-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein said ring isoptionally substituted with oxo, halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘). In some such embodiments, R^(∘) is as defined above anddescribed herein. In certain embodiments, the present invention providesa compound of formula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 3-9membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 6-12 membered saturated or partially unsaturated fused orbridged bicyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein: a substitutablecarbon atom of Cy is optionally substituted with halogen,—(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom ofCy is optionally substituted with —R^(†); wherein R^(∘) is hydrogen orC₁₋₆ aliphatic optionally substituted by halogen or —(CH₂)₀₋₂OR^(●),wherein R^(●) is C₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In somesuch embodiments, two independent occurrences of R^(∘) may be optionallytaken together with their intervening atom(s), form a 3-12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 3-9 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein said ring is optionally substituted with oxo, halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₄OR^(∘). In some such embodiments, R^(∘) is asdefined above and described herein. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(n)OCywhere Cy is a 3-9 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom of Cyis optionally substituted with halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom of Cy is optionallysubstituted with —R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphaticoptionally substituted by halogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) isC₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments,two independent occurrences of R^(∘) may be optionally taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 6-12 memberedsaturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein said ring is optionallysubstituted with oxo, halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘). In somesuch embodiments, R^(∘) is as defined above and described herein. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is a 6-12 memberedsaturated or partially unsaturated fused or bridged bicyclicheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein: a substitutable carbon atom of Cyis optionally substituted with halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), and a substitutable nitrogen atom of Cy is optionallysubstituted with —R^(†), wherein R^(∘) is hydrogen or C₁₋₆ aliphaticoptionally substituted by halogen or —(CH₂)₀₋₂OR^(●), wherein R^(●) isC₁₋₄ aliphatic, and R^(†) is C₁₋₆ aliphatic. In some such embodiments,two independent occurrences of R^(∘) may be optionally taken togetherwith their intervening atom(s), form a 3-12-membered saturated,partially unsaturated, or aryl mono- or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆ aliphatic, whereineach R^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●). In some suchembodiments, R^(●) is C₁₋₄ aliphatic. In certain embodiments, thepresent invention provides a compound of one of formulas I or Illwherein R³ is C₁₋₆ aliphatic substituted by —(CH₂)₀₋₄OR^(∘), whereinR^(∘) is hydrogen. In certain embodiments, the present inventionprovides a compound of one of formulas I or HI wherein R³ is C₁₋₆aliphatic substituted by —(CH₂)₀₋₄OR^(∘), wherein R^(∘) is C₁₋₆aliphatic, wherein each R^(∘) may be substituted by halogen,—(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) isC₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(m)OR, wherein R is hydrogen oroptionally substituted C₁₋₆ aliphatic. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—(CH₂)_(m)OR, wherein R is hydrogen. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(m)OR,wherein R is optionally substituted C₁₋₆ aliphatic. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(m)OR, wherein R is C₁₋₆ aliphatic substituted withoxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘) is as defined aboveand described herein. In certain embodiments, the present inventionprovides a compound of formula I′ wherein R³ is —(CH₂)_(m)OR, wherein Ris C₁₋₆ alkyl substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘)is as defined above and described herein. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—(CH₂)_(m)OR, wherein R is C₁₋₆ alkyl substituted with oxo, halogen,—CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), —(CH₂)₀₋₄N(R^(∘))₂, or—(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is C₁₋₆ aliphatic or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R^(∘)is optionally substituted with —(CH₂)₀₋₂R^(●), wherein R^(●) is C₁₋₄aliphatic. In certain embodiments, the present invention provides acompound of formula I′ wherein R is —(CH₂)_(m)OR, wherein R is ethylsubstituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘) is as defined aboveand described herein. In certain embodiments, the present inventionprovides a compound of formula I′ wherein R³ is (CH₂)_(m)OR, wherein Ris C₁₋₆ aliphatic substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is independentlyhydrogen or C₁₋₆ aliphatic, wherein each R^(∘) may be substituted byhalogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) is asdefined above and described herein. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —(CH₂)_(m)OR,wherein R is ethyl substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄N(R^(∘))₂, or —(CH₂)₀₋₄S(O)₂R^(∘), whereinR^(∘) is C₁₋₆ aliiphatic or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein R^(∘) is optionallysubstituted with —(CH₂)₀₋₂R^(●), wherein R^(●) is C₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound of oneof formulas I or In wherein R³ is C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄N(R^(∘))₂, wherein each R^(∘) is independently hydrogen or C₁₋₆aliphatic, wherein each R^(∘) may be substituted by halogen,—(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋ ₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) isC₁₋₄ aliphatic. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is C₁₋₆ aliphaticsubstituted by —(CH₂)₀₋₄N(R^(∘))₂, wherein each R^(∘) is hydrogen. Incertain embodiments, the present invention provides a compound of one offormulas I or III wherein R³ is C₁₋₆ aliphatic substituted by—(CH₂)₀₋₄N(R^(∘))₂, wherein each R^(∘) is C₁₋₆ aliphatic, wherein eachR^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●). In some suchembodiments, R^(●) is C₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(m)N(R^(∘))₂, wherein each R isindependently hydrogen or optionally substituted C₁₋₆ aliiphatic. Incertain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(m)N(R^(∘))₂, wherein each R ishydrogen. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)N(R^(∘))₂, wherein each Ris optionally substituted C₁₋₆ aliphatic. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—(CH₂)_(m)N(R^(∘))₂, wherein R is C₁₋₆ aliphatic substituted with oxo,halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘).In some such embodiments, R^(∘) is as defined above and describedherein. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)N(R)₂, wherein each R isC₁₋₆ alkyl substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘)is as defined above and described herein. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—(CH₂)_(m)N(R^(∘))₂, wherein each R is C₁₋₆ alkyl optionally substitutedwith oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is C₁₋₆ aliphatic. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(m)N(R^(∘))₂, wherein each R is ethyl substitutedwith oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘) is as defined aboveand described herein. In certain embodiments, the present inventionprovides a compound of formula I′ wherein R³ is —(CH₂)_(m)N(R)₂, whereineach R is ethyl substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is C₁₋₆aliphatic. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)N(R)₂, wherein R is C₁₋₆aliphatic substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is C₁₋₆aliphatic, wherein each R^(∘) may be substituted by halogen,—(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) isC₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound of oneof formulas I or III, wherein R³ is —CH₂N(R^(∘))₂, wherein each R^(∘) isindependently hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6membered heteroaryl ring), or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; wherein R^(∘) may be substituted byhalogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) isC₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound offormula I′, wherein R³ is —CH₂N(R)₂. In certain embodiments, the presentinvention provides a compound of formula I′, wherein R³ is —CH₂N(R)₂,wherein each R is independently hydrogen or optionally substituted C₁₋₆aliphatic. In certain embodiments, the present invention provides acompound of formula I′, wherein R³ is —CH₂N(R^(∘))₂, wherein each R isindependently hydrogen or C₁₋₆ aliphatic substituted with oxo, halogen,—CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘). In some suchembodiments, R^(∘) is as defined above and described herein. In certainembodiments, the present invention provides a compound of formula I′,wherein R³ is —CH₂N(R)₂, wherein each R is independently hydrogen orC₁₋₆ aliphatic optionally substituted with oxo, halogen, —CN,—(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘)is C₁₋₆ aliphatic. In certain embodiments, the present inventionprovides a compound of formula I′, wherein R³ is —CH₂N(R)₂, wherein eachR is independently hydrogen or C₁₋₆ aliphatic substituted with oxo,halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘).In some such embodiments, R^(∘) is as defined above and describedherein. In certain embodiments, the present invention provides acompound of formula I′, wherein R³ is —CH₂N(R)₂, wherein each R isindependently hydrogen or C₁₋₆ aliphatic optionally substituted withoxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘), wherein R^(∘) is C₁₋₆ aliphatic, or two R groups onthe same nitrogen are taken together with the nitrogen to form a 3-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is C₁₋₆ aliphatic substituted by—CH₂OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆ aliphatic, wherein eachR^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●). In some suchembodiments, R^(●) is C₁₋₄ aliphatic. In certain embodiments, thepresent invention provides a compound of one of formulas I or IIIwherein R³ is C₁₋₆ aliphatic substituted by —CH₂OR^(∘), wherein R^(∘) ishydrogen. In certain embodiments, the present invention provides acompound of one of formulas I or III wherein R³ is C₁₋₆ aliphaticsubstituted by —CH₂OR^(∘), wherein R^(∘) is C₁₋₆ aliphatic, wherein eachR^(∘) may be substituted by halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●). In some suchembodiments, R^(●) is C₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —CH₂OR, wherein R is hydrogen or optionallysubstituted C₁₋₆ aliphatic. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —CH₂OR,wherein R is hydrogen. In certain embodiments, the present inventionprovides a compound of formula I′ wherein R³ is —CH₂OR, wherein R isoptionally substituted C₁₋₆ aliphatic. In certain embodiments, thepresent invention provides a compound of formula I′ wherein R³ is—CH₂OR, wherein R is C₁₋₆ aliphatic substituted with oxo, halogen, —CN,—(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)_(0_4)S(O)₂R^(∘). In some suchembodiments, R^(∘) is as defined above and described herein. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —CH₂OR, wherein R is C₁₋₆ aliphatic substituted with oxo,halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘),wherein R^(∘) is C₁₋₆ aliphatic. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —CH₂OR,wherein R is C₁₋₆ alkyl substituted with oxo, halogen, —CN,—(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR, or —(CH₂)₀₋₄S(O)₂R^(∘). In someembodiments, R^(∘) is as defined above and described herein. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —CH₂OR, wherein R is C₁₋₆ alkyl substituted with oxo,halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘),wherein R^(∘) is C₁₋₆ aliphatic. In certain embodiments, the presentinvention provides a compound of formula I′ wherein R³ is —CH₂OR,wherein R is ethyl substituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘),—(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘). In some such embodiments, R^(∘)is as defined above and described herein. In some embodiments of formulaI′, R³ is —CH₂OR, wherein R is ethyl substituted with oxo, halogen, —CN,—(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or —(CH₂)₀₋₄S(O)₂R^(∘), R^(∘) is C₁₋₆aliphatic. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —CH₂OR, wherein R is C₁₋₆ aliphaticsubstituted with oxo, halogen, —CN, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), or—(CH₂)₀₋₄S(O)₂R^(∘), wherein each R^(∘) is independently hydrogen orC₁₋₆ aliphatic, wherein R^(∘) may be substituted by halogen,—(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●),—(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branchedalkylene)C(O)OR^(●), or —SSR^(●). In some such embodiments, R^(●) isC₁₋₄ aliphatic.

In certain embodiments, the present invention provides a compound of oneof formulas I or III wherein R³ is —(CH₂)_(m)Cy where Cy is optionallysubstituted piperidinyl. In certain embodiments, the present inventionprovides a compound of one of formulas I or III wherein R³ is—(CH₂)_(m)Cy where Cy is piperidinyl optionally substituted with oxo,halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), wherein R^(∘) is as definedabove and described herein. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—(CH₂)_(m)Cy where Cy is piperidinyl optionally substituted with oxo,halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), wherein each R^(∘) isindependently C₁₋₆ aliiphatic, wherein two independent occurrences ofR^(∘) may be optionally taken together with their intervening atom(s),form a 3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, the presentinvention provides a compound of one of formulas I or III wherein R³ is—(CH₂)_(n)OCy where Cy is optionally substituted oxetanyl. In certainembodiments, the present invention provides a compound of one offormulas I or III wherein R³ is —(CH₂)_(n)OCy where Cy is oxetanyloptionally substituted with oxo, halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), wherein R^(∘) is C₁₋₆ aliphatic. In certainembodiments, the present invention provides a compound of one offormulas I or Ill wherein R³ is —(CH₂)_(n)OCy where Cy is oxetanyloptionally substituted with oxo, halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), wherein R^(∘) is C₁₋₆ aliphatic, wherein twoindependent occurrences of R^(∘) may be optionally taken together withtheir intervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, the present invention provides a compound of one offormulas I or II wherein R³ is —(CH₂)_(n)OCy where Cy is oxetanyloptionally substituted with oxo, halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), wherein each R^(∘) is C₁₋₆ aliiphatic, wherein twoindependent occurrences of R^(∘) may be optionally taken together withtheir intervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is (CH₂)_(m)Cy where Cy is optionally substitutedpiperidinyl. In certain embodiments, the present invention provides acompound of formula I′ wherein R³ is —(CH₂)_(m)Cy where Cy ispiperidinyl optionally substituted with oxo, halogen, —(CH₂)₀₋₄R^(∘), or—(CH₂)₀₋₄OR^(∘), wherein each R^(∘) is C₁₋₆ aliphatic, wherein twoindependent occurrences of R^(∘) may be optionally taken together withtheir intervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(n)OCy where Cy is optionally substituted oxetanyl.In certain embodiments, the present invention provides a compound offormula I′ wherein R³ is —(CH₂)_(n)OCy where Cy is oxetanyl optionallysubstituted with oxo, halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘),wherein each R^(∘) is C₁₋₆ aliphatic, wherein two independentoccurrences of R^(∘) may be optionally taken together with theirintervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, the present invention provides a compound of formula I′wherein R³ is —(CH₂)_(n)OCy where Cy is oxetanyl optionally substitutedwith oxo, halogen, —(CH₂)₀₋₄R^(∘), or —(CH₂)₀₋₄OR^(∘), wherein eachR^(∘) is C₁₋₆ aliphatic, wherein two independent occurrences of R^(∘)may be optionally taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments, the present invention provides a compound offormula I selected from those depicted in Table 1, below. In certainembodiments, the present invention provides a compound of formula Iselected from those depicted in Table 1 below, wherein the compound isnot I-1. In certain embodiments, the present invention provides acompound of formula I′ selected from those depicted in Table 1, below.In certain embodiments, the present invention provides a compound offormula I′ selected from those depicted in Table 1 below, wherein thecompound is not I-1.

TABLE 1 Compound # Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

In some embodiments, the present invention provides a compound depictedin Table 1, or a pharmaceutically acceptable salt thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, adjuvant, orvehicle. In certain embodiments, the amount of compound in compositionsof this invention is such that it is effective to measurably inhibitMK2, or a mutant thereof, in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

Compounds and compositions, according to method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided herein (i.e., an MK2-mediated disease or disorder).The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. Compounds of the invention are preferably formulated in unitdosage form for ease of administration and uniformity of dosage.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally, intraperitoneally, intracistemallyor via animplanted reservoir. In some embodiments, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

In some embodiments, provided pharmaceutically acceptable compositionsare formulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this invention are administered without food.In other embodiments, pharmaceutically acceptable compositions of thisinvention are administered with food. Pharmaceutically acceptablecompositions of this invention may be orally administered in any orallyacceptable dosage form including, but not limited to, capsules, tablets,aqueous suspensions or solutions. In the case of tablets for oral use,carriers commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried cornstarch. When aqueous suspensions are required for oral use,the active ingredient is combined with emulsifying and suspendingagents. If desired, certain sweetening, flavoring or coloring agents mayalso be added.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and/or i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of kinase activity of one or more enzymes. Examples ofkinases that are inhibited by the compounds and compositions describedherein and against which the methods described herein are useful includeMK2, or a mutant thereof.

The activity of a compound utilized in this invention as an inhibitor ofa MK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo orin a cell line. In vitro assays include assays that determine inhibitionof either the phosphorylation activity and/or the subsequent functionalconsequences, or ATPase activity of activated MK2 kinase, or a mutantthereof. Alternate in vitro assays quantitate the ability of the testcompound to bind to MK2. Inhibitor binding may be measured byradiolabeling the test compound prior to binding, isolating the testcompound/MK2 complex and determining the amount of radiolabel bound.Alternatively, inhibitor binding may be determined by running acompetition experiment where test compounds are incubated with MK2kinase bound to known radioligands. Detailed conditions for assaying acompound utilized in this invention as an inhibitor of MK2, or a mutantthereof, are set forth in the Examples, below.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting MK2 kinase, or a mutant thereof, activity in a biologicalsample comprising the step of contacting said biological sample with acompound of this invention, or a composition comprising said compound.In certain embodiments, the invention relates to a method ofirreversibly inhibiting MK2 kinase, or a mutant thereof, activity in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting MK2 kinase, or a mutant thereof, activity in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method ofirreversibly inhibiting MK2 kinase, or a mutant thereof, activity in apatient comprising the step of administering to said patient a compoundof the present invention, or a composition comprising said compound. Inother embodiments, the present invention provides a method for treatingan MK2-mediated disease or disorder, in a patient in need thereof,comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

MK2 Kinase

MAP kinase-activated protein kinase 2 (“MK2”) is an enzyme that inhumans is encoded by the MAPKAPK2 gene. This gene encodes a member ofthe Ser/Thr protein kinase family. This kinase is regulated throughdirect phosphorylation by p38 MAP kinase. In conjunction with p38 MAPkinase, this kinase is known to be involved in many cellular processesincluding stress and inflammatory responses, nuclear export, geneexpression regulation and cell proliferation. Heat shock protein HSP27was shown to be one of the substrates of this kinase in vivo. Twotranscript variants encoding two different isoforms have been found forthis gene.

MK2 is a multi-domain protein consisting of an N-terminal proline-richdomain, a catalytic domain, an autoinhibitory domain and at theC-terminus a nuclear export signal (NES) and nuclear localization signal(NLS). Two isoforms of human MK2 have been characterized. One isoformconsists of 400 amino acids and the other isoform 370 residues which isthought to be a splice variant missing the C-terminal NLS. MK2 islocated in the nucleus of the cell and upon binding and phosphorylationby p38, the MK2 NES becomes functional and both kinases areco-transported out of the nucleus to the cytoplasm. Interestingly,transport of the MK2/p38 complex does not require catalytically activeMK2, as the active site mutant, Asp207Ala, is still transported to thecytoplasm. Phosphorylation of human MK2 by p38 on residues T222, S272and T334 is thought to activate the enzyme by inducing a conformationalchange of the autoinhibitory domain thus exposing the active site forsubstrate binding. Mutations of two autoinhibitory domain residues W332Aand K326E in murine MK2 demonstrate an increase in basal activity and aC-terminal deletion of the autoinhibitory domain renders the enzymeconstitutively active, providing additional evidence to the role of thisdomain in inhibition of MK2 activity.

Diseases or disorders associated with MK2 that are treated by compoundsof the present invention include autoimmune disorders, chronicinflammatory disorders, acute inflammatory disorders, auto-inflammatorydisorders, fibrotic disorders, metabolic disorders, neoplasias, orcardiovascular or cerebrovascular disorders. Thus, in some embodiments,the present invention provides a method for treating an MK2-mediateddisease or disorder in a patient in need thereof, wherein said methodcomprises administering to said patient a therapeutically effectiveamount of a provided compound, or composition thereof. Such MK2-mediateddiseases or disorders include, but are not limited to those describedherein.

In some embodiments, the MK2-mediated disease or disorder is anautoimmune disorder, chronic and/or acute inflammatory disorder, and/orauto-inflammatory disorder. Exemplary autoimmune and/or inflammatoryand/or auto-inflammatory disorders include: inflammatory bowel diseases(for example, ulcerative colitis or Crohn's disease), multiplesclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis,juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosingspondylitis, cryopyrin associated periodic syndromes, Muckle-Wellssyndrome, familial cold auto-inflammatory syndrome, neonatal-onsetmultisystem inflammatory disease, TNF receptor associated periodicsyndrome, acute and chronic pancreatitis, atherosclerosis, gout,ankylosing spondylitis, fibrotic disorders (for example, hepaticfibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis,scleroderma, anaphylaxis, diabetes (for example, diabetes mellitus type1 or diabetes mellitus type 2), diabetic retinopathy, Still's disease,vasculitis, sarcoidosis, pulmonary inflammation, acute respiratorydistress syndrome, wet and dry age-related macular degeneration,autoimmune hemolytic syndromes, autoimmune and inflammatory hepatitis,autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, Sjogren's syndrome, familial Mediterranean fever, systemiclupus erythematosus, vasculitis syndromes (for example, temporal,Takayasu's and giant cell arteritis, Behçet's disease or Wegener'sgranulomatosis), vitiligo, secondary hematologic manifestation ofautoimmune diseases (for example, anemias), drug-induced autoimmunity,Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic pupura,metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmunedeafness (for example, Meniere's disease), Goodpasture's syndrome,Graves' disease, HW-related autoimmune syndromes, Gullain-Barre disease,Addison's disease, anti-phospholipid syndrome, asthma, atopicdermatitis, Celiac disease, Cushing's syndrome, dermatomyositis,idiopathic adrenal adrenal atrophy, idiopathic thrombocytopenia,Kawasaki syndrome, Lambert-Eaton Syndrome, pernicious anemia,pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primarysclerosing cholangitis, Raynaud's, Reiter's Syndrome, relapsingpolychondritis, Schmidt's syndrome, thyrotoxidosis, sepsis, septicshock, endotoxic shock, exotoxin-induced toxic shock, gram negativesepsis, toxic shock syndrome, glomerulonephritis, peritonitis,interstitial cystitis, hyperoxia-induced inflammations, chronicobstructive pulmonary disease (COPD), vasculitis, graft vs. hostreaction (for example, graft vs. host disease), allograft rejections(for example, acute allograft rejection or chronic allograft rejection),early transplantation rejection (for example, acute allograftrejection), reperfusion injury, pain (for example, acute pain, chronicpain, neuropathic pain, or fibromyalgia), chronic infections,meningitis, encephalitis, myocarditis, gingivitis, post surgical trauma,tissue injury, traumatic brain injury, enterocolitis, sinusitis,uveitis, ocular inflammation, optic neuritis, gastric ulcers,esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis,myositis, polymyalgia, pneumonia and bronchitis.

In some embodiments, the MK2-mediated disease or disorder is a fibroticdisorder. Exemplary fibrotic disorders include systemicsclerosis/scleroderma, lupus nephritis, connective tissue disease, woundhealing, surgical scarring, spinal cord injury, CNS scarring, acute lunginjury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosisor cystic fibrosis), chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension-induced nephropathy, alimentarytrack or gastrointestinal fibrosis, renal fibrosis, hepatic or biliaryfibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis,hepatitis C, or hepatocellular carcinoma), cirrhosis (for example,primary biliary cirrhosis or cirrhosis due to fatty liver disease (forexample, alcoholic and nonalcoholic steatosis)), radiation-inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),primary sclerosing cholangitis, restenosis, cardiac fibrosis (forexample, endomyocardial fibrosis or atrial fibrosis), opthalmicscarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma,fibroadenomas, fibrosarcomas, transplant arteriopathy, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the MK2-mediated disease or disorder is a metabolicdisorder. Exemplary metabolic disorders include obesity,steroid-resistance, glucose intolerance, and metabolic syndrome.

In some embodiments, the MK2-mediated disease or disorder is aneoplasia. Exemplary neoplasias include cancers. In some embodiments,exemplary neoplasias include angiogenesis disorders, multiple myeloma,leukemias (for example, acute lymphocytic leukemia, acute and chronicmyelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, or promyelocytic leukemia), lymphomas (for example, B-celllymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma,Burkitt's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin'sdisease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma,thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratoma,rhabdomyosarcoma, metastatic and bone disorders, as well as cancer ofthe bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon,rectum, lung (for example, non-small cell lung cancer or small cell lungcancer), liver, pancreas, nerve, brain (for example, glioma orglioblastoma multiforme), head and neck, throat, ovary, uterus,prostate, testis, bladder, kidney, breast, gall bladder, cervix,thyroid, prostate, and skin.

In some embodiments, the MK2-mediated disorder is a cardiovascular orcerebrovascular disorder. Exemplary cardiovascular disorders includeatherosclerosis, restenosis of an atherosclerotic coronary artery, acutecoronary syndrome, myocardial infarction, cardiac-allograft vasculopathyand stroke. Exemplary cerebrovascular diseases include central nervoussystem disorders with an inflammatory or apoptotic component,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia andperipheral neuropathy.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Enantioenriched compounds of the invention were prepared inenantioenriched form using chiral starting materials, or were separatedafter reaction with a racemic starting material, using chiralchromatography. For compounds prepared as racemic or diastereomericmixtures, the single isomers can be prepared in optically pure form byeither employing chiral starting materials or performing chiralchromatography.

In the illustrative examples that follow, reactions were carried out atroom or ambient temperature, in the range of 18-25° C. unless otherwisestated. Organic solutions were dried over anhydrous magnesium sulfate orsodium sulfate and evaporation of solvent was carried out using a rotaryevaporator under reduced pressure. In general, the courses of reactionswere followed by TLC or LCMS and reaction times are representative.Yields are given for illustration only and are not necessarily thosewhich can be obtained by diligent process development.

Microwave reactions were performed in a Biotage Explorer reactionmicrowave system. ¹H NMR data is in delta values for major diagnosticprotons, given in parts per million (ppm) relative to tetramethylsilane(TMS) or residual solvent. ¹H NMR spectra were determined at 400 MHz.Solvent ratios are given in volume:volume (v/v) terms. Mass spectra (MS)data was generated on an LCMS system where the HPLC component comprisedgenerally either an Agilent or Shimadzu LCMS-2020 Instrument and was runon a Sepax BR-C18 (4.6×50 mm, 3 μm) column or similar, eluting withacidic eluent (for example, using a gradient between 0-95%water/acetonitrile with 0.1% formic acid or trifluoroacetic acid).Chromatograms were in electrospray (ESI) positive, negative and/or UV.LCMS values for m/z are provided throughout and generally, only ionswhich indicate the parent mass are reported. Unless otherwise stated thevalue quoted is the (M+H) or (M+1) for positive ion mode. PreparativeHPLC was performed on C₁₈ reversed-phase silica using decreasingly polarmixtures as eluent, for example decreasingly polar mixtures of water andacetonitrile containing 1% trifluoroacetic acid.

Enantioenriched intermediates and final compounds were synthesized usingcommercially available chiral materials and their stereochemistry asrecorded is absolute. Unless otherwise specified, starting materialswere commercially available or synthesized according to known methods.

Table of abbreviations TFA trifluoroacetic acid TLC thin layerchromatography THF tetrahydrofuran DMF N,N-dimethylformamide EtOAc ethylacetate DCM dichloromethane DMSO dimethylsulfoxide ACN/MeCN acetonitrilemCPBA m-chloroperoxybenzoic acid DIPEA N,N-diisopropylethylamine(Hünig's base) TBAF tetra-N-butylammonium fluoride PMB p-methoxybenzylrac racemic DMAP 4-dimethylaminopyridine dba dibenzylideneacetone dppf1,1'-bis(diphenylphosphino) ferrocene Xantphos4,5-Bis(dipbenylphosphino)-9,9-dimethylxanthene DavePhos2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl SPhos2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl BINAP(±)-2,2′-Bis(diphenylphosphino )-1,1′-binaphthyl BrettPhos-G1Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2- aminoethyl)phenyl]palladium(II) hhour min minute aq aqueous g gas sat saturated

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth Table 1, supra.

Synthesis of Common Intermediates

S1—Step 1: Synthesis of 6-aminoquinoline-5-carbonitrile (S1-2)

To a solution of 6-nitroquinoline (100 g, 0.57 mol) in dimethylformamide(1 L), potassium hydroxide (96.4 g, 1.7 mol) and ethyl cyanoacetate(183.3 mL, 1.7 mmol) were added and the reaction was stirred at roomtemperature for 48 h. After completion, the reaction mixture wasconcentrated under reduced pressure. To the resulting residue, 30% HCl(1.0 L) was added and stirred at 100° C. for 3 h. The reaction mixturewas cooled to 0° C. and basified with 2N sodium hydroxide (800 g)solution, and a solid formed. The solid was filtered and washed withwater. It was then dissolved in 20 volumes of ethyl acetate and heatedto 60° C. and treated with charcoal (20.0 g) at for 1 h. The reactionmixture was filtered through celite and concentrated under reducedpressure. The yellow solid obtained was dried to afford the titlecompound S1-2 (55.0 g, 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.84 (br s,2H), 7.26 (d, J=9.3 Hz, 1H), 7.51 (dd, J=4.2 Hz, 8.3 Hz, 1H), 7.90 (d,J=9.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 8.60 (d, J=4.2 Hz, 1H). MS m/z(M+H): 170.1.

S1—Step 2: Synthesis of 6-bromoquinoline-5-carbonitrile (S1-3)

To a solution of 6-aminoquinoline-5-carbonitrile (S1-2) (55.0 g, 325mmol) in acetonitrile (1.3 L), tert-butyl nitrite (102 mL, 858.5 mmol)was added at 0° C. The resulting reaction mixture was stirred at 0° C.for 1 h. Then copper (II) bromide (115 g, 520 mmol) was added at 0° C.and stirred and then warmed to 60° C. for 12 h. The reaction mixture wasthen cooled to room temperature and water (2.5 L) was added. Thismixture was extracted with 2% chloroform in methanol (2.5 L). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The solid that had formed while concentratingwas filtered and dried to afford the title compound S1-3 (45.0 g, 62%)as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.85 (dd, J=4.2 Hz, 8.5Hz, 1H), 8.15 (d, J=9.1 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.48 (d, J=8.5Hz, 1H), 9.10 (d, J=3.6 Hz, 1H). MS m/z (M+H): 233.2.

S1—Step 3: Synthesis of methyl 1-aminothieno[3,2-f]quinoline-2-carboxylate (S1-4)

To a solution of 6-bromoquinoline-5-carbonitrile (S1-3) (45.0 g, 193mmol) in methanol (500 mL), sodium methoxide (20.8 g, 386 mmol) wasadded followed by methyl thioglycolate (30.7 g, 289.6 mmol) at roomtemperature. The resulting reaction mixture was stirred at 90° C. for 4h. After completion, the reaction mixture was concentrated under reducedpressure. The residue obtained was diluted with water and stirred for 15min at room temperature, after which time a solid formed. The solid wasfiltered and dried to afford the title compound S1-4 (40 g, 80%) as ayellow color solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.84 (s, 3H), 7.09 (brs, 2H), 7.68 (dd, J=4.2 Hz, 8.5 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 8.15(d, J=8.9 Hz, 1H), 8.93 (d, J=3.5 Hz, 1H), 9.12 (d, J=8.5 Hz, 1H). MSm/z (M+H): 259.0

S1-Step 4: Synthesis of Methyl 1-bromothieno[3,2-f]quinoline-2-carboxylate (S1-5)

To a solution of methyl 1-aminothieno [3,2-f]quinoline-2-carboxylate(S1-4) (40 g, 154.8 mmol) in acetonitrile (1000 mL), tert-butyl nitrite(27.6 mL, 232 mmol) was added dropwise at 0° C. and stirred for 1 h at0° C. To the resulting mixture, copper (II) bromide (41.5 g, 185.8 mmol)was added portionwise at 0° C. and stirred at room temperature for 3 h.After completion, the reaction mixture was diluted with water (3.0 L)and extracted with 2% methanol in chloroform (3.0 L). The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford the title compound S1-5 (20 g, 40%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.93 (s, 3H), 7.77 (dd, J=4.2 Hz, 8.7Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 9.02 (d, J=3.1Hz, 1H), 10.10 (d, J=8.8 Hz, 1H). MS m/z (M+H): 323.9.

S1—Step 5: Synthesis of Methyl1-[[(2R)-2-(tert-butoxycarbonylamino)propyl]amino]thieno[3,2-f]quinoline-2-carboxylate(S1-6)

To a solution of methyl 1-bromothieno [3,2-f]quinoline-2-carboxylate(S1-5) (14 g, 43.4 mmol) in toluene (140 mL), cesium carbonate (28.3 g,86.9 mmol) and (R)-tert-butyl 1-aminopropan-2-ylcarbamate (11.3 g, 65.0mmol, prepared as described in Scheme 2, below) were added at roomtemperature and degassed for 15 min. To the resulting mixture, BINAP(2.7 g, 4.3 mmol) and Pd₂(dba)₃ (3.9 g, 4.3 mmol) were added at roomtemperature and again degassed for 10 min. The resulting reactionmixture was stirred at 110° C. for 16 h. After completion, the reactionmixture was filtered through celite and washed with ethyl acetate andconcentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford the title compound S1-6 (12g, 66%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.01 (d,J=6.5 Hz, 3H), 1.34 (s, 9H), 3.12 (m, 2H), 3.63 (m, 1H), 3.88 (s, 3H),6.55 (t, J=7.0 Hz, 1H), 6.71 (br s, 1H), 7.70 (dd, J=4.2 Hz, 8.3 Hz,1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.94 (d, J=3.9 Hz,1H), 9.04 (d, J=8.3 Hz, 1H). MS m/z (M+H): 416.1.

S1—Step 6: Synthesis of methyl1-[[(2R)-2-aminopropyl]amino]thieno[3,2-f]quinoline-2-carboxylatetrifluoroacetate (S1-7)

To a solution of methyl1-[[(2R)-2-(tert-butoxycarbonylamino)propyl]amino]thieno[3,2-f]quinoline-2-carboxylate(S1-6) (11 g, 26.0 mmol) in dichloromethane (120 mL), trifluoroaceticacid (24.0 g, 211.8 mmol) was added at 0° C. The resulting reactionmixture was stirred at 25° C. for 2 h. After completion, the reactionmixture was concentrated under reduced pressure, co-distilled withdichloromethane (3×20 mL) to afford the title compound S1-7 (9.0 g,crude) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.26 (d,J=6.2 Hz, 3H), 3.16-3.19 (m, 1H), 3.36-3.49 (m, 2H), 3.92 (s, 3H), 6.39(br s, 1H), 7.76 (dd, J=4.2 Hz, 8.5 Hz, 1H), 7.86 (br s, 2H), 8.09 (d,J=9.0 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.99 (d, J=4.2 Hz, 1H), 9.10 (d,J=8.5 Hz, 1H). MS m/z (M+H): 316.1.

S1—Step 7: Synthesis of(14R)-14-Methyl-20-thia-16,17,18-triazatetracyclooctadeca-2(6),3(8),4,9(16),10,12-hexaen-15-one(S1-8)

To a solution of trifluoroacetate salt of methyl1-[[(2R)-2-aminopropyl]amino]thieno[3,2-f]quinoline-2-carboxylate (S1-7)(9.0 g, 28.5 mmol) in methanol (640 mL), sodium methoxide (7.7 g, 142.7mmol) was added at room temperature. The resulting reaction mixture wasstirred at 90° C. for 12 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The residue obtained was dilutedwith water and stirred for 15 min, during which time a solid had formed.The solid was filtered and dried under vacuum to afford the titlecompound S1-8 (4.5 g, 55%) as a green solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.18 (d, J=6.7 Hz, 3H), 3.46 (d, J=2.4 Hz, 2H), 3.59-3.61 (m, 1H),7.06 (br s, 1H), 7.64 (dd, J=4.2 Hz, 8.5 Hz, 1H), 7.94 (d, J=8.8 Hz,1H), 8.00 (br s, 1H), 8.09 (d, J=8.9 Hz, 1H), 8.89 (d, J=4.0 Hz, 1H),9.15 (d, J=8.5 Hz, 1H). MS m/z (M+H): 284.1.

S1—Step 8: Synthesis of di-tert-butyl(20R)-20-methyl-21-oxo-34-thia-26,27,28-triazatetracyclooctadeca-8(12),9(14),10,15(26),16,18-hexaene-27,28-dicarboxylate(S1-9)

To a solution of(14R)-14-methyl-20-thia-16,17,18-triazatetracyclooctadeca-2(6),3(8),4,9(16),10,12-hexaen-15-one(S1-8) (4.5 g, 15.9 mmol) in dichloromethane (100 mL),4-dimethylaminopyridine (0.5 g, 4.0 mmol) and triethylamine (5.5 mL,39.7 mmol) were added at room temperature. The reaction was stirred for10 min then di-tert-butyldicarbonate (15.5 mL, 67.5 mmol) was added atroom temperature and stirring was continued for 4 h. After completion,the reaction mixture was diluted with dichloromethane and washed withwater. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford the title compound S1-9 (6.8g, 88%) as a white solid. MS m/z (M+H): 484.2.

S1—Step 9: Synthesis of di-tert-butyl(20R)-20-methyl-26-oxido-21-oxo-35-thia-27,28-diaza-26-azoniatetracyclooctadeca-8(12),9(14),10,15(26),16,18-hexaene-27,28-dicarboxylate (S1-10)

To a solution of di-tert-butyl(20R)-20-methyl-21-oxo-34-thia-26,27,28-triazatetracyclooctadeca-8(12),9(14),10,15(26),16,18-hexaene-27,28-dicarboxylate (S1-9) (6.8 g, 14.0 mmol) indichloromethane (200 mL), m-chloroperoxybenzoic acid (3.6 g, 21.0 mmol)was added portionwise at 0° C. The resulting reaction mixture wasstirred at 30° C. for 3 h. After completion, the reaction mixture wasdiluted with ice cold water and extracted with dichloromethane. Thedichloromethane layer was washed with sodium bicarbonate solution, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue obtained was triturated with diethyl ether to afford thetitle compound S1-10 (6.5 g, 92%) as a pale yellow solid. MS m/z (M+H):500.1.

S1-Step 10: Synthesis of dl-tert-butyl(20R)-16-chloro-20-methyl-21-oxo-34-thia-26,27,28-triazatetracyclooctadeca-8(13),9,11(16),14(26),15(17),18-hexaene-27,28-dicarboxylate(S1-11)

To a solution of di-tert-butyl(20R)-20-methyl-26-oxido-21-oxo-35-thia-27,28-diaza-26-azoniatetracyclooctadeca-8(12),9(14),10,15(26), 16,18-hexaene-27,28-dicarboxylate (S1-10) (4.0 g, 8.0 mmol)in dimethylformamide (100 mL), oxalyl chloride (1.03 mL, 12.0 mmol) wasadded dropwise at 0° C. The resulting reaction mixture was stirred atroom temperature for 2 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The residue obtained was dilutedwith water and stirred for 5 min. during which time a solid formed. Thesolid was isolated by filtration and washed with petroleum ether toafford the title compound Si-11 (3.9 g, 93%) as an off-white solid. MSm/z (M+H): 518.1.

S1-Step 11: Synthesis of(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12)

To a solution of di-tert-butyl(20R)-16-chloro-20-methyl-21-oxo-34-thia-26,27,28-triazatetracyclooctadeca-8(13),9,11(16),14(26),15(17),18-hexaene-27,28-dicarboxylate (S1-11) (3.0 g, 5.8 mmol)in dichloromethane (30.0 mL), trifluoroacetic acid (3.3 g, 28.9 mmol)was added dropwise at 0° C. The resulting reaction mixture was stirredat room temperature for 2 h. After completion, the reaction mixture wasconcentrated under reduced pressure and co-distilled withdichloromethane three times. The residue obtained was basified withsaturated sodium bicarbonate solution (pH8), and a solid was formed. Thesolid was filtered and dried to afford the title compound S1-12 (1.8 g,96%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7 Hz,3H), 3.44 (m, 2H), 3.59 (m, 1H), 7.07 (br s, 1H), 7.72 (d, J=8.9 Hz,1H), 7.89 (d, J=8.9 Hz, 1H), 8.10 (d, J=4.1 Hz, 1H), 8.20 (d, J=8.9 Hz,1H), 9.21 (d, J=8.9 Hz, 1H). MS m/z (M+H): 318.2.

A solution of compound S1-4 (200 g, 775 mmol) in DMF (7.75 L) was cooled0° C. under nitrogen. NaH (37.2 g, 930 mmol, 60% in mineral) was addedin portions over 0.5 h. The mixture was stirred at 0° C. for another 0.5h and compound S2-6 (185.5 g, 783 mmol) was added in portions over 0.5h. After addition was complete, TLC analysis showed the startingmaterial nearly consumed. Water (4 L) was added slowly and the mixturewas stirred for 10 min. Then aqueous HCl (4 L, 1 N) was added and themixture was stirred at room temperature for 1 h. Na₂CO₃ was added toadjust pH 8 and the resulting solid was collected by filtration, washedwith water and then dissolved in DCM (2.0 L). The organic phase wasseparated, dried over anhydrous sodium sulfate and concentrated. Theresidue was slurried in ethyl acetate (2.0 L) for 1 h and then filtered.The filtration cake was dried under vacuum to afford compound S1-6 (196g, yield 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 1.01 (d,J=6.5 Hz, 3H), 1.34 (s, 9H), 3.12 (m, 2H), 3.63 (m, 1H), 3.88 (s, 3H),6.55 (t, J=7.0 Hz, 1H), 6.71 (br, 1H), 7.70 (dd, J=4.2 Hz, 8.3 Hz, 1H),8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.94 (d, J=3.9 Hz, 1H),9.04 (d, J=8.3 Hz, 1H). MS m/z (M+H): 416.1.

A solution of compound S1-6 (450 g, 1.08 mol) in DCM (5.4 L) was cooledto 0° C. TFA (989 g, 8.67 mol) was added dropwise and the reactionmixture was stirred at room temperature overnight. The mixture waspoured into aqueous NaHCO₃(1.0 kg in 10.0 L of H₂O) with stirring. Twophases were separated and the aqueous phase was extracted with DCM. Theorganic phases were combined, washed with water, dried over anhydroussodium sulfate and concentrated to afford compound S1-7 as the free base(330 g, yield 96%) as a brown oil. ¹H NMR (400 MHz, DMSO-d6): δ 1.07 (d,J=6.4 Hz, 3H), 3.08 (m, 1H), 3.12 (m, 2H), 3.95 (s, 3H), 6.67 (t, J=6.0Hz), 7.52 (m, 1H), 7.92 (d, 8.8 Hz, 1H), 8.06 (d, 8.8 Hz, 1H), 8.92 (m,1H), 9.15 (d, J=8.4 Hz, 1H).

To a solution of S1-7 free base (170 g, 0.54 mol) in methanol (9 L) wasadded sodium methoxide (29 g, 0.54 mol). The reaction mixture wasstirred at 70° C. overnight and then concentrated. Water (7.0 L) wasadded and the resulting mixture was stirred for 20 min and filtered. Thefilter cake was washed with water, dried under vacuum and then slurriedin DCM (3.0 L) for 1 h. The mixture was filtered and the filter cake waswashed with DCM and dried under vacuum to afford compound S1-8 (274 g,yield 90%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d,J=6.7 Hz, 3H), 3.46 (d, J=2.4 Hz, 2H), 3.59-3.61 (m, 1H), 7.06 (br s,1H), 7.64 (dd, J=4.2 Hz, 8.5 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 8.00 (brs, 1H), 8.09 (d, J=8.9 Hz, 1H), 8.89 (d, J=4.0 Hz, 1H), 9.15 (d, J=8.5Hz, 1H). MS m/z (M+H): 284.1.

S2—Step 1: Synthesis of (R)-2-(tert-butoxycarbonylamino)propylmethanesulfonate (S2-2)

To a stirred solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate(S2-1) (10.0 g, 57 mmol) in dichloromethane (100 mL), triethylamine(8.65 g, 86 mmol) and methanesulfonylchloride dissolved indichloromethane (5 mL, 63 mmol) were added dropwise at 0° C. Theresulting solution was stirred for 2 h after which time the reactionmixture was partitioned between dichloromethane (200 mL) and water (100mL). The organic phase was washed with 0.1M HCl solution (50 mL), sodiumbicarbonate solution (50 mL) and brine (50 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the title compound S2-2 (12 g, 83%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (d, J=6.6 Hz, 3H), 1.37 (s, 9H),3.15 (s, 3H), 3.73 (m, 1H), 4.03 (d, J=5.8 Hz, 2H), 6.92 (d, J=7.6 Hz,1H).

S2—Step 2: Synthesis of (S)-tert-butyl 1-azidopropan-2-ylcarbamate(S2-3)

To a solution of (R)-2-(tert-butoxycarbonylamino)propyl methanesulfonate(S2-2) (12 g, 47 mmol) in dimethylsulfoxide (75.0 mL), sodium azide (3.7g, 57 mmol) was added slowly at room temperature. The resulting mixturewas heated to 45° C. for 24 hours. The reaction mixture was thenpartitioned between dichloromethane (200 mL) and ice-cold water (100mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the title compound S2-3(6.0 g, 64%) as a light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 1.02 (d,J=6.0 Hz, 3H), 1.37 (s, 9H), 3.20 (d, J=6.0 Hz, 2H), 3.64 (m, 1H), 6.84(br s, 1H).

S2—Step 3: Synthesis of (R)-tert-butyl 1-aminopropan-2-ylcarbamate(S2-4)

To a stirred solution of (S)-tert-butyl 1-azidopropan-2-ylcarbamate(S2-3) (6.0 g, 30 mmol) in ethyl acetate (50.0 mL), 10% Pd/C (2.3 g) wasadded. The reaction mixture was stirred under a hydrogen atmosphere (1atm) for 15 h at room temperature. The reaction mixture was filteredthrough celite, the celite was washed with ethyl acetate and thefiltrate was concentrated under reduced pressure to obtain the titlecompound S2-4 (4.8 g, 92%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 0.95 (d, J=6.6 Hz, 3H), 1.36 (s, 9H), 2.49 (m, 2H), 3.32 (m,1H), 6.49 (br s, 1H).

A solution of (R)-aminopropan-1-ol (100 g, 1.33 mol) in methanol (1.0 L)was cooled to 0° C. TEA (278 mL, 2.0 mol) and Boc₂O (320 g, 1.47 mol)were added. The reaction mixture was warmed to room temperature andstirred for 1 h. The mixture was concentrated and the residue wasdissolved in DCM (1.0 L). The resulting solution was washed withsaturated aqueous NH₄Cl. The aqueous phase was re-extracted with DCM(0.2 L). The organic phases were combined, washed with saturated aqueousNH₄Cl, dried over anhydrous sodium sulfate and concentrated to affordcompound S2-1 as a viscous oil (240 g), which was used in the next stepwithout further purification.

A solution of imidazole (562 g, 8.26 mol) in DCM (5.5 L) was cooled to0° C. To this solution was added a solution of thionyl chloride (180 mL,2.48 mol) in DCM (1.9 L) dropwise over 0.5 h. The cooling bath wasremoved and the mixture was stirred at room temperature for 1 h. Themixture was cooled to −10° C. and a solution of compound S2-1 (obtainedfrom the above step) in DCM (2.6 L) was added dropwise. The cooling bathwas removed and the reaction mixture was stirred at room temperature for10 min. Aqueous citric acid (7.2 L, 10%) was added and the resultingmixture was stirred for 15 min. The organic phase was separated, washedwith brine (10 L), dried over anhydrous sodium sulfate and concentratedto afford compound S2-5 as a mixture of diastereomers, which was used inthe next step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ1.29 (d, J=6.4 Hz, 1.6H), 1.50 (d, J=6.0 Hz, 1.5H), 1.53 (s, 9H), 4.06(m, 0.5H), 4.31 (m, 1H), 4.68 (t, J=9.6 Hz, 0.5H), 4.79 (t, J=9.2 Hz,0.5H), 5.02 (m, 0.5H).

To a solution of crude compound S2-5 (320 g) in acetonitrile (5.0 L) wasadded RuCl₃ (150 mg, 0.725 mmol) followed by a solution of NaIO₄ (310 g,1.45 mol) in water (3.3 L). The reaction mixture was stirred at roomtemperature for 40 min and then diluted by addition of DCM (5.0 L) andwater (5.0 L). The organic phase was separated, washed with brine, driedover anhydrous sodium sulfate and concentrated to afford compound S2-6(218 g) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.51 (d, J=6.4 Hz,3H), 1.56 (s, 9H), 4.20 (dd, J=9.2 Hz, 6.4 Hz, 1H), 4.42 (m, 1H), 4.67(dd, J=8.8 Hz, 6.0 Hz, 1H).

Synthesis of(S)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1)

The title compound was synthesized in the same manner as(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12), substituting (S)-tert-butyl4-(aminomethyl)-2,2-dimethyloxazolidine-3-carboxylate for (R)-tert-butyl(1-aminopropan-2-yl)carbamate. This gave the title compound INT-1. SeeAnderson, D.; Meyers, M. et al. Bioorganic & Medicinal Chemistry Letters19 (2009) 4878-4881.

Synthesis of (R)-tert-butyl3-amino-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-12(9H)-carboxylate(INT-2)

A solution of (R)-di-tert-butyl3-chloro-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepino-[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate(S1-11) (400 mg, 0.7 mmol) in THF was treated with Pd₂(dba) (76 mg, 0.07mmol) and 2-(dicyclohexylphosphino)biphenyl (65 mg, 0.18 mmol) in asealed tube. The resulting solution was briefly degassed by applyingvacuum and then flushed with nitrogen thrice. Then lithiumhexamethyldisilazide (1.0 M in THF) (1.9 mL, 1.9 mmol) was added at roomtemperature. The reaction mixture was stirred at 65° C. for 1 h. Aftercompletion, the reaction mixture was quenched with cold water (10.0 mL),and extracted with ethyl acetate (3×15 mL). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude material obtained was purified by silica gelchromatography to afford the title compound INT-2 (180 mg, 58%) as abrown solid. MS m/z (M+H): 399.1.

Synthesis of(R)-3-amino-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-3)

(R)-tert-butyl3-amino-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-12(9H)-carboxylate(INT-2) (8.0 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) andstirred at room temperature. To this solution, trifluoroacetic acid (0.5mL, 6.49 mmol) was added. The reaction was stirred at room temperaturefor one hour after which the volatiles were removed under reducedpressure. The resulting residue was redissolved in dichloromethane,concentrated onto silica gel, and purified by silica gel chromatography(8:1 MeOH/NH₄OH in dichloromethane (0-10%) to afford the title compoundINT-3 (4.0 mg, 67% yield). MS: m/z 299.0 (M+H)^(J)H NMR (400 MHz,DMSO-d₆): δ 9.01 (d, 1H), 8.04 (d, 1H), 7.88 (d, 1H), 6.96 (d, 1H), 6.45(m, 1H), 3.68 (m, 2H), 3.52 (m, 1H), 1.36 (d, 3H).

Synthesis of (R)-dl-tert-butyl3-bromo-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate(INT-4)

To a solution of(R)-9,12-bis(tert-butoxycarbonyl)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline4-oxide (S1-10) (2.5 g, 5.0 mmol) in dimethylformamide (70.0 mL),phosphorus oxybromide (2.15 g, 7.5 mmol) was added portionwise at 0° C.The resulting reaction mixture was stirred at room temperature for 2 h.After completion of reaction, the reaction mixture was concentratedunder reduced pressure. The residue obtained was diluted with water andstirred for 5 min, and a solid was formed. The obtained solid wasfiltered and washed with petroleum ether to afford the title compoundINT-4 (2.4 g, 78%) as an off-white solid. MS m/z (M+H): 562.1.

Synthesis of(R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-5)

To a solution of (R)-di-tert-butyl3-bromo-10-methyl-8-oxo-0,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate(INT-4) (1.4 g, 2.5 mmol) in dichloromethane (90.0 mL), trifluoroaceticacid (36.0 mL, 12.4 mmol) was added dropwise at 0° C. The resultingreaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure and co-distilled with dichloromethane thrice. The crudesolid obtained was diluted with saturated sodium bicarbonate solution at0° C. to pH˜8 and stirred for 10 min. In this time a solid formed. Thesolid was filtered and dried to afford the title compound INT-5 (830 mg,88%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7 Hz,3H), 3.44 (s, 2H), 3.60 (br s, 1H), 7.05 (br s, 1H), 7.81 (d, J=8.9 Hz,1H), 7.90 (d, J=8.9 Hz, 1H), 8.06 (d, J=3.16 Hz, 1H), 8.19 (d, J=8.9 Hz,1H), 9.10 (d, J=8.9 Hz, 1H). MS m/z (M+H): 362.0.

Synthesis of(R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino-[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-6)

In a 10 mL microwave vial(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one,synthesized in Scheme 1A (S1-12) (0.1 g, 0.315 mmol) was suspended in 3mL of glacial acetic acid with 1 mL H₂O. The vial was sealed andirradiated at 130° C. for 3 h in a Biotage Explorer microwave reactor.The reaction was cooled, the precipitate that had formed was isolated byfiltration, washed 3 times with water and dried under high vacuum. Thefiltrate was concentrated onto silica gel and chromatographed with 8:1MeOH/NH₄OH in dichloromethane (0-10%). The precipitate and productisolated by chromatography were combined to yield the title compoundINT-6 (0.080 g, 0.267 mmol, 85% yield) as a yellow powder.

Large scale synthesis of(R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-H-[1,4]diazepino-[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-6)

(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12, 40 g, 0.126 mol) was suspended in 300 mL of glacial acetic acidwith 100 mL H₂O. The mixture was stirred at 110° C. for 4 d then cooledand concentrated to dryness. Ammonium hydroxide (28-30% aq) (200 mL) wasadded to the residue and the resulting mixture was stirred ar rt for 30min then filtered. The cake was washed with water and dried undervacuum. The crude product was slurried in ethyl acetate (350 mL) for 1 hthen filtered. The cake was dried under vacuum to afford INT-6 as ayellow solid (33 g, 87.6%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (d, J=6.8Hz, 3H), 3.40 (br, 2H), 3.56 (br, 1H), 6.61 (d, J=10.0 Hz, 1H), 6.88(br, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 8.12 (d, J=4.0Hz, 1H), 8.81 (d, J=10 Hz, 1H) 11.99 (br, 1H). MS m/z (M+H): 300.1.

Synthesis of((R)-3-mercapto-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-7)

To a solution of S1-12 (150 mg, 0.5 mmol), in dimethylformamide (2.0mL), sodium hydrosulfide (30% w/v, 52.9 mg, 0.9 mmol) was added at roomtemperature. The resulting reaction mixture was stirred at 100° C. for 5h. After completion, the reaction mixture was quenched with water andacidified with 1N HCl (pH-2), whereupon a solid formed. The solid wasfiltered and dried under vacuum to afford the title compound INT-7 (100mg, 55%) as a yellow color solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (d,J=6.6 Hz, 3H), 3.39 (br s, 2H), 3.56 (br s, 1H), 6.91 (br s, 1H), 7.36(d, J=9.3 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 8.07(br s, 1H), 8.66 (d, J=9.4 Hz, 1H), 13.87 (br s, 1H). MS m/z (M+H):316.2.

Synthesis of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate(INT-8)

In a 15 mL vial, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate(1.00 g, 4.30 mmol) was dissolved in THF (10 mL) and triethylamine (2.00ml, 14.35 mmol) was added, followed by ammonia (2 ml, 4.30 mmol). Theresulting mixture was stirred overnight at room temperature. Aftercompletion of the reaction, the solvents were evaporated and the crudemixture was purified by silica gel chromatography using hexane/ethylacetate (0-40%) as the eluent to give the title compound INT-8 (0.72 g,3.38 mmol, 79% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.55 (s,1H), 8.02 (br s, 1H), 7.64 (br s, 1H), 4.24 (q, 2H), 2.44 (s, 3H), 1.27(t, 3H).

Synthesis of 2-((4,6-difluoropyrimidin-2-yl)oxy)-N,N-dimethylethanamine(S3-2a) and 2-((2,6-difluoropyrimidin-4-yl)oxy)-N,N-dimethylethanamine(S3-2b)

In a 20 mL round-bottomed flask was dissolved 2,4,6-trifluoropyrimidine(S3-1) (0.370 ml, 4.48 mmol) in tetrahydrofuran (8 mL) to give acolorless solution. 2-(dimethylamino)ethanol (0.450 ml, 4.48 mmol) wasadded at −78° C. and the reaction was warmed to room temperature andstirred for 1 h. Upon completion, the reaction was concentrated ontosilica gel and chromatographed with 8:1 MeOH/NH₄OH in dichloromethane(0-10%). The fractions containing product were collected andconcentrated to yield the title compounds (S3-2a) (0.500 g, 2.462 mmol,55% yield) and (S3-2b) (0.045 g, 0.224 mmol, 5% yield) as an inseparablemixture. This mixture was used as-is in subsequent steps.

Synthesis of 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine(S3-3a)

7N ammonia in MeOH (0.352 mL, 2.461 mmol) was added to a solution of2-((4,6-difluoropyrimidin-2-yl)oxy)-N,N-dimethylethanamine (S3-2a) (0.5g, 2.461 mmol) and2-((2,6-difluoropyrimidin-4-yl)oxy)-N,N-dimethylethanamine (S3-2b)(0.045 g, 0.221 mmol) in methanol (3 mL). The reaction was then warmedto 70° C. After 30 min of heating a white precipitate formed. Thereaction was cooled, diluted with dichloromethane and washed withsaturated sodium bicarbonate (aq.). The organic layer was separated andthe aqueous layer was extracted 3 additional times with dichloromethane.The combined organic layers were dried over sodium sulfate andconcentrated to yield a white solid which was recrystallized from ethylacetate and heptane to yield the title compound S3-3a (0.246 g, 1.230mmol, 50% yield).

Synthesis of 6-fluoro-2-(oxetan-3-yloxy)pyrimidin-amine (INT-9a) and4-fluoro-6-(oxetan-3-yloxy)pyrimidin-2-amine (INT-9b)

The title compound was synthesized in the same manner as2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a)substituting oxetan-3-ol for 2-(dimethylamino)ethanol. The reactionmixture was heated to 45° C. and the product was isolated by silica gelchromatography affording the title compound INT-9a (0.266 g, 1.437 mmol,62% yield). A small amount of4-fluoro-6-(oxetan-3-yloxy)pyrimidin-2-amine (INT-9b) was also isolatedas a byproduct.

Synthesis of(rac)-6-fluoro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine (INT-10)

The title compound was synthesized in the same manner as2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a)substituting 1-methylpiperidin-3-ol for 2-(dimethylamino)ethanol. Thereaction mixture was heated to 45° C. and the product was isolated bysilica gel chromatography, affording the title compound INT-10 (20 mg,41% yield) as colorless oil. MS m/z (M+H): 227.0.

Synthesis of6-fluoro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine (INT-11)

The title compound was synthesized in the same manner as2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a)substituting 2-(4-methylpiperazin-1-yl)ethanol for2-(dimethylamino)ethanol. The reaction mixture was heated to 45° C. andthe product was isolated by silica gel chromatography, affording thetitle compound INT-11 (60 mg, 51.6%) as a colorless sticky solid. ¹H NMR(400 MHz, DMSO-d₆): δ 2.34 (s, 3H), 2.34-2.36 (m, 1H), 2.50-2.54 (m,6H), 2.55-2.65 (m, 3H), 4.25 (t, J=5.6 Hz, 2H), 5.63 (s, 1H), 7.19 (brs, 2H). MS m/z (M+H): 256.2.

Synthesis of(R)-6-fluoro-2-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-amine (INT-12)

The title compound was synthesized in the same manner as2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a)substituting (R)-1-methylpyrrolidin-3-ol for 2-(dimethylamino)ethanol.The reaction mixture was heated to 45° C. and the product was isolatedby silica gel chromatography, affording the title compound INT-12 (60mg, 51.6%) (140 mg, 70%) as a white solid. MS m/z (M+H): 213.1.

Synthesis of 4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine(INT-13) and 2,4-difluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidine(INT-14)

In a 20 mL vial (3-methyloxetan-3-yl)methanol (0.744 ml, 7.46 mmol),cesium carbonate (2.430 g, 7.46 mmol), and 2,4,6-trifluoropyrimidine(S3-1) (1 g, 7.46 mmol) were dissolved in 10 mL of dry THF to give acolorless suspension. The reaction was stirred at room temperature for 1hour, poured into saturated sodium bicarbonate (aq.) and extracted 3times with dichloromethane. The combined organic layers were dried oversodium sulfate, decanted, concentrated onto silica gel, and purified bychromatography (0-100% ethyl acetate in heptane) to give an inseparable1.3:1 mixture of isomers INT-13 and INT-14, favoring4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine INT-13. Themixture was used as-is for subsequent steps.

Synthesis of 6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine(INT-15a) and 4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine(INT-15b)

In a 20 mL vial, the mixture isolated above was heated to 40° C.overnight in 10 mL of 7N NH₃ in methanol. Upon completion, the reactionwas cooled and concentrated onto silica gel under reduced pressure.6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (INT-15s) wasisolated by silica gel chromatography (0-100% ethyl acetate in heptane)as the more polar fraction (0.557 g, 2.6 mmol, 35.0% yield). A smallamount of 4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine(INT-15b) was also isolated as a byproduct.

Synthesis of 4,6-difluoro-2-(2-methoxyethoxy)pyrimidine (INT-16) and2,4-difluoro-6-(2-methoxyethoxy)pyrimidine (INT-17)

The title compound was synthesized in the same manner as4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine (INT-13)substituting 2-methoxyethanol for (3-methyloxetan-3-yl)methanol. Thisgave an inseparable mixture (1:1) of the title compounds INT-17 andINT-16 as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ 6.24 (s, 1H),6.15 (s, 1H), 4.50 (m, 2H), 4.48 (m, 2H), 3.71 (m, 4H), 3.39 (s, 6H).

Synthesis of 4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-amine (INT-18) and6-fluoro-2-(2-methoxyethoxy)pyrimidin-4-amine (INT-19)

In a 20 mL vial, a mixture (1:1) of2,4-difluoro-6-(2-methoxyethoxy)pyrimidine (INT-17) and4,6-difluoro-2-(2-methoxyethoxy)pyrimidine (INT-16) was then heated to65° C. in 10 mL of 30% NH₃ in water. Upon completion, the reaction wascooled, extracted thrice with dichloromethane, and the combined organicextracts were dried over sodium sulfate. The organic fraction was thenconcentrated onto silica gel and purified by silica gel chromatography(0-100% ethyl acetate in heptane) to give the title compounds INT-18 ¹HNMR (400 MHz, DMSO-d6): δ 5.62 (1H), 5.09 (br s, 2H), 4.40 (m, 2H), 3.69(m, 2H), 3.39 (s, 3H) and INT-19 ¹H NMR (400 MHz, DMSO-d6): δ 5.67 (1H),5.10 (br s, 2H), 4.42 (m, 2H), 3.67 (m, 2H), 3.40 (s, 3H) as separatefractions.

Synthesis of (S)-2,4-difluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidine(INT-20) and (S)-4,6-difluoro-2-((tetrahydrofran-3-yl)oxy)pyrimidine(INT-21) (1.00:0.77)

The title compounds were synthesized in the same manner as4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine (INT-13)substituting (S)-tetrahydrofuran-3-ol for (3-methyloxetan-3-yl)methanol.An inseparable mixture of(S)-2,4-difluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidine (INT-20) and(S)-4,6-difluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidine (INT-21)(1.00:0.77) was isolated and used directly in the next step. ¹H NMR (400MHz, CDCl₃): δ 6.19 (s, 1H), 6.17 (s, 1H), 5.60 (m, 1H), 5.47 (m, 1H),3.98 (m, 4H), 3.91 (m, 4H), 2.27 (m, 2H), 2.24 (m, 2H).

Synthesis of (S)-4-fluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine(INT-22) and (S)-6-fluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-amine(INT-23) (1.00:0.77)

The title compound was synthesized in the same manner as4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-amine (INT-18) and6-fluoro-2-(2-methoxyethoxy)pyrimidin-4-amine (INT-19) to give a mixtureof the title compounds INT-22 ¹H NMR (400 MHz, DMSO-d6): δ 7.04 (br s,2H), 5.66 (s, 1H), 5.44 (m, 1H), 3.84-3.72 (m, 4H), 2.20-2.15 (m, 1H),1.97-1.95 (m, 1H) and INT-23 ¹H NMR (400 MHz, DMSO-d6): δ 7.23 (br s,2H), 5.63 (s, 1H), 5.31 (m, 1H), 3.83-3.71 (m, 4H), 2.17-2.12 (m, 1H),1.95-1.92 (m, 1H) which were separated by silica gel chromatography(0-100% ethyl acetate in heptane).

Synthesis of (R)-2,4-difluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidine(INT-24) and (R)-4,6-difluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidine(INT-25) (1.3:1)

The title compounds were synthesized in the same manner as4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine (INT-13)substituting (R)-tetrahydrofuran-3-ol for (3-methyloxetan-3-yl)methanol.An inseparable mixture of(R)-2,4-difluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidine (INT-24) and(R)-4,6-difluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidine (INT-25)(1.3:1) was isolated and used directly in the next step. ¹H NMR (400MHz, CDCl₃): δ 6.19 (s, 1H), 6.17 (s, 1H), 5.60 (m, 1H), 5.48 (m, 1H),3.98 (m, 4H), 3.91 (m, 4H), 2.30 (m, 2H), 2.20 (m, 2H).

Synthesis of (R)-4-fluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amineand (R)-6-fluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-amine (1.3:1)

The title compound was synthesized in the same manner as4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-amine (INT-18) and6-fluoro-2-(2-methoxyethoxy)pyrimidin-4-amine (INT-19), starting from amixture of (R)-2,4-difluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidine(INT-24) and (R)-4,6-difluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidine(INT-25) to give a mixture of the title compounds INT-26 ¹H NMR (400MHz, CDCl₃): δ 5.64 (s, 1H), 5.43 (m, 1H), 5.13 (br s, 2H), 4.05-3.88(m, 4H), 2.18-2.16 (m, 2H) and INT-27 ¹H NMR (400 MHz, CDCl₃): δ 5.61(s, 1H), 5.49 (m, 1H), 5.10 (br s, 2H), 3.96-3.86 (m, 4H), 2.21-2.11 (m,2H) which were separated by silica gel chromatography (0-100% ethylacetate in heptane).

S4—Step 1: Synthesis of N-tert-butyl-6-chloro-2-iodo-pyrimidin-4-amine(S4-2)

To a stirred solution of sodium hydride (122 mg, 5.1 mmol) and2-methylpropan-2-amine (399 mg, 5.4 mmol) in tetrahydrofuran (15.0 mL),was added 4,6-dichloro-2-iodo-pyrimidine (S4-1) (1.0 g, 3.6 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 5h. After completion, the reaction mixture was diluted with ethyl acetateand washed with water. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude materialobtained was purified by silica gel chromatography (100-200 mesh) using2-5% ethyl acetate/petroleum ether to afford the title compound S4-2(480 mg, 42.3%) as a pale yellow solid. MS m/z (M+H): 312.0.

S4—Step 2: Synthesis of(rac)-N-tert-butyl-6-chloro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine(S4-3)

To a solution of sodium hydride (18 mg, 0.7 mmol) in tetrahydrofuran(10.0 mL) were added (rac)-1-methylpiperidin-3-ol (85 mg, 0.7 mmol) andN-tert-butyl-6-chloro-2-iodo-pyrimidin-4-amine (S4-2) (200 mg, 0.6 mmol)at 0° C. The resulting reaction mixture was stirred at room temperaturefor 24 h. After completion, the reaction mixture was concentrated underreduced pressure. The crude material was purified by silica gel columnchromatography using 5% methanol in dichloromethane to afford the titlecompound S4-3 (100 mg, 52%) as a gummy liquid. MS: m/z 299.1 (M+H).

S4—Step 3: Synthesis of(rac)-6-Chloro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine (S4-4)

To a stirred solution of(rac)-N-tert-butyl-6-chloro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine(S4-3) (25 mg, 0.1 mmol) in dichloromethane (6.0 mL), was added sulfuricacid (4.1 mg, 0.04 mmol) at 0° C. The resulting reaction mixture wasstirred at 60° C. for 1 h. After completion, the reaction mixture wasbasified with aqueous ammonia solution and extracted withdichloromethane. The organic layer was washed with water, brinesolution, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to afford the title compound S4-4 (10 mg, 49%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.33-1.34 (m, 2H),1.42-1.51 (m, 1H), 1.67-1.71 (m, 1H), 1.87-1.89 (m, 1H), 1.99-2.02 (m,2H), 2.15 (s, 3H), 2.75-2.81 (m, 1H), 4.81-4.87 (m, 1H), 6.08 (s, 1H),7.12 (br s, 2H). MS: m/z 243.1 (M+H).

Synthesis of(R)-6-chloro-2-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-amine (INT-28)

The title compound was synthesized in the same manner as(rac)-6-chloro-2-[(l-methyl-3-piperidyl)oxy]pyrimidin-4-amine (S4-4)substituting (R)-1-methylpyrrolidin-3-ol for(rac)-1-methylpiperidin-3-ol in Step 2 of the synthesis of S4-4 to givethe title compound INT-28 (90 mg, 58%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.76-1.80 (m, 1H), 2.20-2.27 (m, 1H), 2.31 (s,3H), 2.43-2.45 (m, 1H), 2.62-2.65 (m, 1H), 2.71-2.75 (m, 1H), 2.83-2.88(m, 1H), 5.19-5.22 (m, 1H), 6.10 (s, 1H), 7.13 (br s, 2H). MS m/z (M+H):229.1.

S5-Step 1: Synthesis of2,6-dichloro-N-(4-methoxybenzyl)pyrimidin-4-amine (S5-2)

To a solution of 2,4,6-trichloropyrimidine (2.0 g, 0.01 mol mmol) int-butanol (5.0 mL), triethylamine (2.2 g, 0.02 mol) and p-methoxybenzylamine (1.6 g, 0.012 mol) were added at 0° C. The resulting reactionmixture was stirred at 75° C. for 4 h. After completion, the reactionmixture was concentrated under reduced pressure. The crude materialobtained was diluted with dichloromethane, and washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The solid obtained was purified bycolumn chromatography with 1-10% ethyl acetate in petroleum ether toafford the title compound S5-2 (650 mg, 17%) as an off-white solid. ¹HNMR: (400 MHz, DMSO-d₆): δ 3.72 (s, 3H), 4.42 (d, J=4.8 Hz, 2H), 6.54(s, 1H), 6.89 (d, J-=8.8 Hz, 2H), 7.23 (d J=8.8 Hz., 2H), 8.51 (br s,1H). MS m/z (M+H): 284.3.

S-Step 2: Synthesis of6-chloro-N-(4-methoxybenzyl)-2-(2-methoxyethoxy)pyrimidin-4-amine (S5-3)

To a solution of 2,6-dichloro-N-(4-methoxybenzyl)pyrimidin-4-amine(S5-2) (750 mg, 2.6 mmol) in tetrahydrofuran (15.0 mL), sodium hydride(76.02 mg, 3.2 mmol) was added at 0° C. and stirred for 10 min. To theresulting mixture, 2-ethoxyetbanol (241.01 mg, 3.2 mmol) was added at 0°C. The reaction was allowed to warm to 25° C. and stirred for 12 h.After completion, the reaction mixture was diluted with ice cold water(30.0 mL) and extracted with ethyl acetate (2×50 mL). The organic layerwas washed with brine (50.0 mL) solution, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudematerial obtained was purified by column chromatography with 20% ofethyl acetate in hexane to afford the title compound S5-3 (550 mg, 64%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.26 (s, 3H), 3.57 (t,J=4.7 Hz, 2H), 3.72 (s, 3H), 4.29 (t, J=4.6 Hz, 2H), 4.42 (br s, 2H),6.20 (s, 1H), 6.89 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 8.09 (brs, 1H). MS m/z (M+H): 324.1.

S5—Step 3: Synthesis of 6-chloro-2-(2-methoxyethoxy)pyrimidin-4-amine(S5-4)

A solution of6-chloro-N-(4-methoxybenzyl)-2-(2-methoxyethoxy)pyrimidin-4-amine (S5-3)(350 mg, 1.1 mmol) in dichloromethane (10.0 mL) was cooled to 0° C. andsulfuric acid (212.05 mg, 2.1 mmol) was added at 0° C. The resultingreaction mixture was stirred at room temperature for 30 min. Aftercompletion, the reaction mixture was quenched with ammonia solution andextracted with dichloromethane (2×100 mL). The organic layer was washedwith 2×50 mL water, followed by 20 mL saturated brine solution. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under educed pressure. The crude material obtained waspurified by preparative TLC to afford the title compound S5-4 (200 mg,89%) as a white solid. MS m/z (M+H): 204.1.

Synthesis of6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine (INT-29)

The title compound was synthesized in the same manner as6-chloro-2-(2-methoxyethoxy)pyrimidin-4-amine (S5-4) substituting2-(4-methylpiperazin-1-yl)ethanol for 2-methoxyethanol in S5—Step 2 togive 6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amineINT-29 (120 mg, 57%) as a white solid. MS m/z (M+H): 272.3.

S6-step 1: Synthesis of 4,6-dichloro-2-iodo-pyrimidine (S6-2)

To a solution of 4,6-dichloropyrimidin-2-amine (S6-1) (5.0 g, 30.5 mmol)in tetrahydrofuran (40.0 mL), copper(I) iodide (5.8 g, 30.5 mmol),diiodomethane (41.6 g, 155.5 mmol) and isoamyl nitrite (10.7 g, 91.4mmol) were added at room temperature. The resulting reaction mixture wasstirred at 80° C. for 3 h. After completion, it was filtered through acelite bed and the filtrate was concentrated under reduced pressure. Thecrude material obtained was dissolved in ethyl acetate (60 mL) andwashed with water (2×30 mL) followed by brine solution (30 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material obtained waspurified by silica gel column chromatography with 10% ethyl acetate inhexane to afford the title compound S6-2 (4.2 g, 50%) as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 7.38 (s, 1H).

S6—Step 2: Synthesis of6-chloro-2-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine (S6-3)

To a solution of 4,6-dichloro-2-iodo-pyrimidine (S6-2) (2.0 g, 7.3 mmol)in t-butanol (20.0 mL), triethylamine (1.47 g, 14.5 mmol) andp-methoxybenzyl amine (1.0 g, 7.3 mmol) were added at room temperature.The resulting reaction mixture was stirred at 70° C. for 2 h. Aftercompletion, the reaction mixture was concentrated under reducedpressure. The residue obtained was dissolved in ethyl acetate (20.0 mL)and the organic layer was washed with water (2×10 mL) followed bysaturated brine solution (1×10 mL). The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography with 10%ethyl acetate in hexane to afford the title compound S6-3 (1.8 g, 65%)as an off-white solid. MS m/z (M+H): 376.1.

S6—Step 3: Synthesis of methyl4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-2-carboxylate (S6-4)

To a solution of 6-chloro-2-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine(56-3) (1.0 g, 2.6 mmol) in methanol (8.0 mL), triethylamine (1.1 mL,8.0 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (108.6 mg, 0.1 mmol) were added at roomtemperature. The resulting reaction mixture was stirred at 80° C. underCO(g) atmosphere for 5 h. After completion, the reaction was filteredthrough celite and the filtrate was concentrated under reduced pressure.The residue obtained was dissolved in ethyl acetate (20.0 mL), and theorganic layer was washed with water (2×10 mL) followed by brine (1×10mL) solution. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The crude material was purified byflash column chromatography eluting in 5% ethyl acetate in hexane toafford the title compound S6-4 (800 mg, 97%) as a brown liquid. MS m/z(M+H): 308.2.

S6—Step 4: Synthesis of methyl 4-amino-6-chloropyrimidine-2-carboxylate(S6-5)

Methyl 4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-2-carboxylate(S6-4) (400 mg, 1.3 mmol) was cooled to 0° C. and trifluoroacetic acid(0.2 mL, 6.5 mmol) and trifluoromethanesulfonic acid (0.2 mL, 6.5 mmol)were added at 0° C. The resulting reaction mixture was stirred at roomtemperature for 30 min. After completion, the reaction was concentratedunder reduced pressure. The residue obtained was diluted with saturatedsodium bicarbonate solution and extracted with dichloromethane (20.0mL). The organic layer was washed with 2×10 mL water followed by 10 mLsaturated brine solution. The organic layer was then dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The crudematerial was purified by flash column chromatography with 1% methanol inchloroform to afford the title compound S6-5 (110 mg, 45%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.81 (s, 3H), 6.51 (s, 1H), 7.57 (brs, 2H).

S7—Step 1: Synthesis of N⁴-tert-Butyl-6-fluoro-pyrimidine-2,4-diamine(S7-2)

In a sealable tube, a solution of 4,6-difluoropyrimidin-2-amine (1.0 g,7.6 mmol) in 1,4-dioxane/dimethylformamide (20.0 mL, 1:1), potassiumcarbonate (1.6 g, 11.9 mmol) and tert-butylamine (1.7 g, 23.0 mmol) wereadded. The resulting reaction mixture was stirred at room temperaturefor 48 h. After completion, the reaction mixture was concentrated underreduced pressure. The crude material was diluted with cold water (10.0mL) whereupon a solid formed. The solid was filtered and air dried toafford the title compound S7-2 (1.2 g, 85%) as an off-white solid. MSm/z (M+H): 185.1.

S7—Step 2: Synthesis of N-tert-Butyl-6-fluoro-2-iodo-pyrimidin-4-amine(S7-3)

To a solution of N⁴-tert-butyl-6-fluoro-pyrimidine-2,4-diamine (57-2)(2.1 g, 11.4 mmol) in tetrahydrofuran (10.0 mL), copper (1) iodide (3.0g, 15.7 mmol), diiodomethane (3.16 mL, 39.2 mmol), and isoamyl nitrite(5.0 mL, 34.2 mmol) were added at room temperature. The resultingreaction mixture was stirred at 70° C. for 2 h. After completion, thereaction mixture was filtered through celite and then concentrated underreduced pressure. The crude material was purified by silica gel columnchromatography to afford the title compound S7-3 (1.5 g, 45%) as a brownoily liquid. MS m/z (M+H): 296.0.

S7—Step 3: Synthesis of methyl4-(tert-butylamino)-6-fluoropyrimidine-2-carboxylate (57-4)

To a solution of N-tert-butyl-6-fluoro-2-iodo-pyrimidin-4-amine (S7-3)(1.5 g, 5.1 mmol) in methanol (20.0 mL), PdCl₂(dppf) (0.33 g, 0.4 mmol),and triethylamine (0.8 g, 7.6 mmol) were added at room temperature. Theresulting reaction mixture was stirred under 20 psi CO for 4 h. Aftercompletion, the reaction mixture was filtered through celite andconcentrated under reduced pressure. The crude material obtained waspurified by silica gel column chromatography to afford the titlecompound S7-4 (800 mg, 69%) as a brown liquid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.39 (s, 9H), 3.83 (s, 3H), 6.20 (s, 1H), 7.72 (br s, 1H).MS m/z (M+H): 228.1.

S7—Step 4: Synthesis of(4-(tert-butylamino)-6-fluoropyrimidin-2-yl)methanol (S7-5)

To a solution of methyl4-(tert-butylamino)-6-fluoropyrimidine-2-carboxylate (S7-4) (800 mg, 3.5mmol) in methanol (20.0 mL), sodium borohydride (1.3 g, 35.2 mmol) wasadded at room temperature and the reaction was stirred for 3 h. Aftercompletion, the reaction mixture was concentrated under reducedpressure. The crude material was dissolved in water (10.0 mL) andextracted with ethyl acetate (2×10.0 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford the title compound S7-5 (600 mg, 86%) as an off-white liquid. MSm/z (M+H): 200.1.

S7—Step 5: Synthesis ofN-(tert-butyl)-6-fluoro-2-(iodomethyl)pyrimidin-4-amine (S7-6)

To a solution of (4-tert-butylamino)-6-fluoropyrimidin-2-yl)methanol(S7-5) (600 mg, 3.0 mmol) in dichloromethane (20.0 mL), imidazole (512mg, 7.5 mmol) and triphenylphosphine (1.6 g, 6.0 mmol) were addedfollowed by the portionwise addition of iodine (382 mg, 1.5 mmol) at 25°C. The resulting reaction mixture was stirred at room temperature for 1h. After completion, the reaction mixture was quenched with saturatedsodium thiosulfite solution (3.0 mL) and extracted with dichloromethane(2×10 mL). The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography to afford the title compoundS7-6 (400 mg, 43%) as a viscous solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.39(s, 9H), 4.22 (s, 2H), 5.89 (s, 1H), 7.45 (br s, 1H).

S7—Step 6: Synthesis ofN-(tert-butyl)-6-fluoro-2-(piperidin-1-ylmethyl)pyrimidin-4-amine (S7-7)

To a solution of piperidine (82.6 mg, 0.97 mmol) in acetonitrile (5.0mL), potassium carbonate (220 mg, 1.6 mmol) was added followed by theaddition of N-(tert-butyl)-6-fluoro-2-(iodomethyl)pyrimidin-4-amine(S7-6) (250 mg, 0.8 mmol) at room temperature. The resulting reactionmixture was stirred at room temperature for 30 min. After completion,the reaction mixture was diluted with water (10.0 mL) and extracted withethyl acetate (2×10 mL). The organic layer was separated, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude material was purified by preparative TLC to affordthe title compound S7-7 (170 mg, 79%) as a pale green liquid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.33-1.36 (m, 2H), 1.38 (s, 9H), 1.44-1.50 (m,4H), 2.44-2.46 (m, 4H), 3.37 (s, 2H), 5.90 (s, 1H), 7.26 (br s, 1H).

S7—Step 7: 6-fluoro-2-(piperidin-1-ylmethyl)pyrimidin-4-amine (S7-8)

To a solution of N-(tert-butyl)-6-fluoro-2-(iodomethyl)pyrimidin-4-amine(S7-7) (170 mg, 0.6 mmol) in dichloromethane (15.0 mL), concentratedH₂SO₄ (0.3 mL) was added at 0° C. The resulting reaction mixture wasstirred at room temperature for 2 h. After completion, dichloromethanewas decanted and to the resulting gummy solid a few drops of NH₃solution were added followed by azeotropic distillation using toluene(2×5 mL) to afford the crude product. The solid was triturated with 10%methanol in chloroform (4×5 mL). The organic layer was separated, driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford the title compound S7-8 (120 mg, 95%) as an off-white solid. MSm/z (M+H): 211.1.

S8—Step 1: Synthesis of(S)-(3-chloro-8-oxo-9,0,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-10-yl)methylmethanesulfonate (S8-2)

To a stirred solution ofS)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1) (50 mg, 0.1 mmol) in dichloromethane (5.0 mL) was addedtriethylamine (0.86 mL, 0.4 mmol) followed by methanesulfonyl chloride(0.24 mL, 0.2 mmol) at 0° C. The resulting reaction mixture was stirredat room temperature for 10 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The resulting crude material wasdiluted with ice cold water, and a solid was formed. The solid wasfiltered and dried to afford compound 58-2 (50 mg, 81%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.18 (s, 3H), 3.42-3.43 (m, 1H),3.85-3.90 (m, 2H), 4.09-4.13 (m, 1H), 4.28-4.32 (m, 1H), 7.13 (br s,1H), 7.72 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.8 Hz,1H), 8.34 (d, J=5.2 Hz, 1H), 9.16 (d, J=8.8 Hz, 1H). MS m/z (M+H):412.2.

S8—Step 2: Synthesis of(S)-10-(azidomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S8-3)

To a stirred solution of(S)-(3-chloro-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-10-yl)methylmethanesulfonate (S8-2) (50.0 mg, 0.1 mmol) in dimethylformamide (2.0mL), was added sodium azide (15.78 mg, 0.2 mmol) at 0° C. The resultingreaction mixture was stirred at 50° C. for 10 h. After completion ofreaction, the reaction mixture was concentrated under reduced pressure.The crude was diluted with ice cold water, whereupon solids formed. Theobtained solids were filtered and dried to afford compound 88-3 (30 mg,69%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.37-3.51 (m,2H), 3.63-3.66 (m, 1H), 3.74-3.79 (m, 1K), 7.15 (br s, 1H), 7.72 (d,J=8.8 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.33 (d,J=5.2 Hz, 1H), 9.17 (d, J=8.8 Hz, 1H). MS m/z (M+H): 359.1.

S8—Step 3: Synthesis of(S)-10-(azidomethyl)-3-((6-fluoropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(58-4)

A solution of(S)-10-(azidomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S8-3) (200 mg, 0.5 mmol) in 1,4-dioxane (6.0 mL) was briefly degassedby applying vacuum and then flushed with nitrogen. To this6-fluoropyrimidin-4-amine (75.4 mg, 0.7 mmol), Pd₂(dba)₃ (50.9 mg, 0.06mmol), Xantphos (32.1 mg, 0.06 mmol) and cesium carbonate (541.9 mg, 1.6mmol) were added sequentially at room temperature. The mixture wasdegassed again and stirred at 90° C. for 10 h. After completion, thereaction mixture was concentrated under reduced pressure. The crudematerial was washed with water, followed by 5% methanol indichloromethane to afford compound 8-4 (80 mg, 32%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.42-3.55 (m, 2H), 3.63-3.66 (m,1H), 3.76-3.80 (m, 1H), 7.07 (br s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.90(d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 8.17 (br s, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.58 (br s, 1H), 9.07 (d, J=8.8 Hz, 1H), 10.92 (br s,1H).

S8—Step 4: Synthesis of (S)-tert-butyl((3-((6-fluoropyrimidin-4-yl)amino)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-10-yl)methyl)carbamate(S8-5)

To a stirred solution of(S)-10-(azidomethyl)-3-((6-fluoropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(58-4) (150 mg, 0.3 mmol) in tetrahydrofuran/water (2:1) (6.0 mL) wasadded triphenylphosphine (270 mg, 1.0 mmol) at room temperature. Theresulting reaction mixture was stirred at 85° C. for 16 h. Aftercompletion the reaction mixture was concentrated under reduced pressure.The crude material was washed with diethyl ether followed by 5% methanolin dichloromethane to afford crude(R)-10-(aminomethyl)-3-((6-fluoropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(100 mg) as a pale yellow solid. The crude material isolated wasdissolved in dimethylformamide (5.0 mL) and triethylamine (86 mg, 0.7mmol) and di-tert-butyl dicarbonate (106 mg, 0.4 mmol) were added atroom temperature. The resulting reaction mixture was stirred at roomtemperature for 10 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC to afford compound 58-5 (20 mg, 11% after 2 steps) as ayellow solid. MS m/z (M+H): 510.1.

Synthesis of6-fluoro-2-((4-methylpiperazin-1-yl)methyl)pyrimidin-4-amine (INT-30)

The title compound was synthesized in the same manner as6-fluoro-2-(piperidin-1-ylmethyl)pyrimidin-4-amine (57-8) substituting1-methylpiperazine for piperidine in S7—Step 6 to give the titlecompound INT-30 (120 mg, 88%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d) (1D₂O Exchange): δ 2.29 (s, 3H), 2.52-2.65 (m, 8H), 3.36 (s,2H), 5.90 (s, 1H), 7.12 (br s, 2H). MS m/z (M+H): 226.2.

Synthesis of 4-chloro-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine(INT-31)

In a 10 mL round-bottomed flask 4,6-dichloro-1,3,5-triazin-2-amine(0.047 g, 0.285 mmol) and 1-methylpiperazine (0.032 ml, 0.285 mmol) weredissolved in tetrahydrofuran (5 mL) to give a colorless solution. Thereaction was warmed to 65° C. and after one hour the reaction becamecloudy. The reaction was cooled and concentrated onto silica gel andchromatographed with 8:1 MeOH/NH₄OH in dichloromethane (0-10%) to yieldthe title compound INT-31 (0.057 g, 0.251 mmol, 88% yield).

Synthesis ofN¹-(6-fluoropyrimidin-4-yl)-N²,N²-dimethylethane-1,2-diamine (INT-32)

In a 10 mL round-bottomed flask, 4,6-difluoropyrimidine (0.305 g, 2.63mmol) and K₂CO₃ (0.363 g, 2.63 mmol) were added to 1,4-dioxane (5 mL) togive a colorless suspension. To this, N¹,N¹-dimethylethane-1,2-diamine(0.287 ml, 2.63 mmol) was added and the reaction was stirred at roomtemperature. After one hour the reaction was concentrated onto silicaand gel and chromatographed with 8:1 MeOH/NH₄OH in dichloromethane(0-10%) to yield the title compound INT-32 (0.290 g, 1.577 mmol, 60%yield).

Synthesis of 6-fluoro-N-(2-methoxyethyl)pyrimidin-4-amine (INT-33)

In a 10 mL round-bottomed flask 4,6-difluoropyrimidine (0.35 ml, 4.13mmol) and Hünig's base (0.722 ml, 4.13 mmol) were dissolved intetrahydrofuran (5 mL) to give a colorless solution. The reaction wascooled to 0° C. and 2-methoxyethanamine (0.322 ml, 4.13 mmol) was added.The reaction was allowed to warm to room temperature and stirred for 3hours. Upon completion the reaction was concentrated onto silica gelpurified by chromatography (0-100% ethyl acetate in heptane) to give thetitle compound INT-33 (0.318 g, 1.859 mmol, 45% yield).

Synthesis of 2,4-dichloro-6-(pyrrolidin-1-yl)-1,3,5-triazine (INT-34)

To 2,4,6-trichloro-1,3,5-triazine (662 mg, 3.59 mmol) in 4 mL THF at 0°C. was added Hünig's base (732 μL, 4.19 mmol) followed by pyrrolidine(100 μL, 1.197 mmol) in 2 mL THF dropwise. The reaction was stirred at0° C. LCMS after 1 h showed the desired mass as the major peak and smallamount of di-pyrrolidine adduct. The crude mixture was filtered,concentrated, and purified by silica gel chromatography (0-25% ethylacetate/heptanes) to give the title compound INT-34 (223 mg, 1.018 mmol.85% yield) as a white solid. MS m/z: 219.1 [M+H].

Synthesis of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (INT-35)

The title compound was synthesized in the same manner as2,4-dichloro-6-(pyrrolidin-1-yl)-1,3,5-triazine (INT-34) substitutingmorpholine for pyrrolidine to give the title compound INT-35 as a whitesolid. MS: m/z 235.1+H).

Synthesis of 2,4-dichloro-6-(piperidin-1-yl)-1,3,5-triazine (INT-36)

To 2,4,6-trichloro-1,3,5-triazine (300 mg, 1.627 mmol) and sodiumcarbonate (259 mg, 2.440 mmol) was added tetrahydrofuran (8 mL) at 0°C., followed by piperdine (163 μl, 1.627 mmol). The reaction mixtureturned cloudy within a few minutes. LCMS after 1 h showed the desiredmass as the major product and some di-addition adduct as the minorproduct. The crude material was filtered, concentrated, and purified bysilica gel chromatography (0-20% ethyl acetate/heptanes) to yield amixture of the title compound (INT-36, major) and di-adduct (minor).LCMS m/z: 233.0 [M+H].

Synthesis of 4,6-dichloro-N,N-dimethyl-1,3,5-triazin-2-amine (INT-37)

To 2,4,6-trichloro-1,3,5-triazine (300 mg, 1.627 mmol) and cesiumcarbonate (689 mg, 2.115 mmol) in tetrahydrofuran (8 mL) was addeddimethylamine (1 M in THF (813 μl, 1.627 mmol)) dropwise at 0° C. After45 min, LCMS showed the desired mass as the major product and a smalleramount of di-addition adduct. The crude mixture was filtered andpurified by silica gel chromatography (0-20% Ethyl acetate/heptanes) toobtain 144 mg mixture of mostly the title compound INT-37 and someundesired 6-chloro-N²,N²,N⁴,N⁴-tetramethyl-1,3,5-triazine-2,4-diamine.The mixture was used in the next step without further purification.

Synthesis of 2,4-dichloro-6-methoxy-1,3,5-triazine (INT-38)

To 2,4,6-trichloro-1,3,5-triazine (300 mg, 1.627 mmol) in MeOH (32.500mL) was added sodium bicarbonate (137 mg, 1.627 mmol) and the mixturewas stirred at room temperature for 45 min. The mixture was then dilutedwith water and extracted with dichloromethane, washed with saturatedNaCl (aq.), dried over sodium sulfate, filtered, and concentrated togive the title compound INT-38 (271 mg, 1.506 mmol, 93% yield) as awhite solid. ¹H-NMR (400 MHz, CDCl₃): δ 4.14 (s, 3H).

Synthesis of 2,4-dichloro-6-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazine(INT-39)

To 2,4,6-trichloro-1,3,5-triazine (150 mg, 0.813 mmol) and cesiumcarbonate (583 mg, 1.789 mmol) in THF (8 mL) at 0° C. was added3,3-difluoropyrrolidine hydrochloride (120 mg, 0.813 mmol) in oneportion. To this was added 2.2 eq (313 μL) of Hünig's base. LCMS after 2h showed the desired mass as the major peak. The reaction mixture wasfiltered, concentrated, and purified by silica gel chromatography (0-10%ethyl acetate/heptanes) to give the title compound INT-39(123 mg, 0.482mmol, 59.3% yield) as a white solid. MS m/z: 254.8 [M+H].

Synthesis of 2,4-dichloro-6-(3,3-difluoropiperidin-1-yl)-1,3,5-triazine(INT-40)

The title compound was synthesized in the same manner as2,4-dichloro-6-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazine (INT-39)substituting 3,3-difluoropiperidine hydrochloride for3,3-difluoropyrrolidine hydrochloride to give the title compound INT-40.MS: m/z 268.9 [M+H].

Synthesis of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxylicacid (INT-41)

In a 20 mL vial (R)-ethyl2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxylate(I-18) (0.112 g, 0.232 mmol) was added to 5 mL of a 4:1 methanol/watersolution. LiOH (0.371 ml, 0.371 mmol) was added and the reaction waswarmed to 35° C. Upon completion, HCl (0.371 ml, 0.371 mmol) was addedand the product precipitated out of solution. The reaction was filtered,and the solids were rinsed with cold water and dried under vacuum toafford compound INT-41 (0.103 g, 0.226 mmol, 98% yield).

Synthesis of (R)-tert-butyl10-methyl-3-((2-(methylsulfonyl)pyrimidin-4-yl)amino)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-12(9H)-carboxylate(INT-42)

To a solution of (R)-tert-butyl3-amino-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-12(9H)-carboxylate(INT-2) (100.0 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL),4-chloro-2-methylsulfonyl-pyrimidine (58.0 mg, 0.3 mmol) and potassiumcarbonate (102.4 mg, 0.7 mmol), were added at room temperature. Theresulting solution was briefly degassed by applying vacuum and thenflushed with nitrogen thrice. Finally, Pd₂(dba)₃ (45.9 mg, 0.05 mmol)and DavePhos (2.5 mg, 0.01 mmol) were added at room temperature and themixture was further degassed. The reaction mixture was allowed to stirat 100° C. for 3 h. After completion of the reaction, the reactionmixture was diluted with water (10.0 mL) and extracted with ethylacetate (2 times, 10.0 mL). The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude material obtained was purified by preparative to afford compoundINT-42 (45 mg, 32%) as a brown solid. MS m/z: 555.2 (M+H).

Synthesis of4-amino-2-chloro-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (INT-43b)

To a stirred solution of2,4-dichloro-N-[(4-methoxyphenyl)methyl]pyrimidine-5-carboxamide(INT-43a, 500 mg, 1.6 mmol, prepared according to the proceduredescribed in WO 2011/090760 A1) in THF (5 mL) was added ammonia (1 mL,24.03 mmol) at 0° C. and stirred at room temperature for 30 min. Aftercompletion, the reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layer was washed with waterfollowed by brine solution, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford 1 (440 mg, 85% yield) as an off whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.71 (s, 3H), 4.35 (d, J=6 Hz, 2H),6.88 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 8.22 (s, br, 2H), 8.54(s, 1H), 9.09 (d, J=5.7 Hz, 1H).

Synthesis of(R)-2-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(INT-43)

The title compound was synthesized in the same manner as I-1substituting INT-43b for 5-fluoro-2-nitroaniline, and(R)-3-bromo-10-methyl-9,10,11,12-tetrabydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-5) for(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one.Heating was done conventionally at 100° C. for 6h (rather than bymicrowave irradiation). This gave(R)-2-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamideINT-43 (141 mg, 88%) as a yellow solid. MS m/z (M+H): 574.1.

Synthesis of(R)-2-chloro-N-(4-methoxybenzyl)-4-(methyl(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(INT-44)

To a stirred solution of(R)-2-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(INT-43) (180 mg, 0.3 mmol) in dimethylformamide (2.0 mL) were addedpotassium carbonate (86.66 mg, 0.6 mmol), potassium iodide (10.4 mg,0.06 mmol), and methyl iodide (66.7 mg, 0.5 mmol) at 0° C. The resultingreaction mixture was stirred at 75° C. for 1 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The crude product was diluted with water, and the solids formed werefiltered and washed with water then dried under vacuum to affordcompound INT-44 (120 mg, 53%) as a yellow solid. MS m/z (M+H): 588.4.

Synthesis of 4-Chloro-6-(2-methoxylxyethoxy) pyrimidin-2-amine (INT-45)

To a solution of 4,6-dichloropyrimidin-2-amine (1.0 g, 6.1 mmol) intetrahydrofuran (20.0 mL), sodium hydride (175.6 mg, 7.3 mmol) was addedat 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min.To the reaction mixture 2-methoxyethanol (556.8 mg, 7.3 mmol) was addedat 0° C. and stirred at room temperature for 4 h. After completion, thereaction mixture was quenched with ice cold water (50 mL), extractedwith ethyl acetate (2×50 mL), and washed with brine (50.0 mL). Theorganic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure to afford 1 (900 mg, 68%) as a pale yellow solid.¹H NMR (400 MHz, DMSO-d₆): δ 3.27 (s, 3H), 3.58-3.61 (m, 2H), 4.33-4.35(m, 2H), 6.08 (s, 1H), 6.96 (br s, 2H). MS m/z (M+H): 204.1.

Synthesis of4-Chloro-6-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-amine (INT-46)

To a suspension of sodium hydride (13.4 mg, 0.3 mmol) in tetrahydrofuran(5.0 mL) was added 2-(4-methylpiperazin-1-yl)ethanol (43.9 mg, 0.3 mmol)at 0° C. The reaction mixture was stirred at room temperature for 30min. A solution of 4,6-dichloropyrimidin-2-amine (50 mg, 0.3 mmol) indimethylformamide (0.5 mL) was added to the reaction mixture at 0° C.The resulting reaction mixture was stirred at room temperature for 3 h.After completion, the reaction mixture was concentrated under reducedpressure. The residue obtained was washed with diethyl ether to affordcompound 1 (20 mg, 24%) as a brown solid. ¹H NMR (400 MHz, DMSO-d): δ2.11 (s, 3H), 2.26 (br s, 4H), 2.41 (br s, 4H), 2.58-2.61 (t, J=5.8 Hz,2H), 4.29-4.32 (t, J=5.9 Hz, 2H), 6.06 (d, J=3.1 Hz, 1H), 6.99 (br s,2H). MS m/z (M+H): 272.1.

Synthesis of(R)-10-(aminomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-47)

To a stirred solution of(S)-10-(azidomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S8-3) (50 mg, 0.1 mmol) in water/tetrahydrofuran (1:3, 4.0 mL) wasadded triphenylphosphine (146 mg, 0.4 mmol) at room temperature. Theresulting reaction mixture was stirred at 85° C. for 16 h. Aftercompletion, the reaction mixture was concentrated under reducedpressure. The crude material was washed with diethyl ether to affordcompound INT-47 (35 mg, 76%) as a pale yellow solid. MS m/z (MI-H):333.2.

Synthesis of(S)-3-chloro-10-((dimethylamino)methyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-48)

To a solution of(R)-10-(aminomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(10.0 mg, 0.03 mmol) (INT-47) in methanol (4.0 mL) was addedformaldehyde (0.01 mL, 0.6 mmol) and the reaction was stirred for 10min. at room temperature. Acetic acid (1.0 μL) and sodiumcyanoborohydride (1.9 mg, 0.03 mmol) were added, and stirring wascontinued at 25° C. for 1 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The crude material was diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water followed by brine. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography using 5% methanol indichloromethane as eluent to afford compound INT-48 (7.0 mg, 64%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.21 (s, 6H), 2.33-2.35 (m,2H), 3.37-3.45 (m, 1H), 3.53-3.62 (m, 1H), 3.63-3.70 (m, 1H), 7.07 (t,J=4.8 Hz, 1H), 7.62 (br s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 9.19 (d, J=9.2 Hz, 1H). MS m/z (M+H):361.3.

Synthesis of(S)-3-chloro-10-(iodomethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(INT-49)

To a stirred solution of(S)-(3-chloro-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-10-yl)methylmethanesulfonate (58-2) (140 mg, 0.3 mmol) in acetone (5.0 mL) was addedsodium iodide (506.46 mg, 3.4 mmol) at room temperature. The resultingreaction mixture was stirred at 60° C. for 16 h. After completion, thereaction mixture was concentrated under reduced pressure. The crudematerial was diluted with ice cold water, whereupon solids formed. Thesolids were filtered and dried to afford compound INT-49 (135 mg, 90%)as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.20-3.24 (m, 1H),3.31-3.35 (m, 1H), 3.42-3.45 (m, 1H), 3.68-3.71 (m, 1H), 3.86-3.89 (m,1H), 7.18 (br s, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),8.20 (d, J=8.8 Hz, 1H), 8.33 (d, J=4.8 Hz, 1), 9.18 (d, J=8.8 Hz 1H). MSm/z (M+H): 444.2.

Synthesis of(R)-3-chloro-10-((methylamino)methyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-50)

A mixture of(S)-3-chloro-10-(iodomethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-49) (20 mg, 0.05 mmol) and methylamine (2M in THF) (1.8 mL, 4 mmol)was stirred at 90° C. for 3 h. The reaction mixture was thenconcentrated under reduced pressure. The crude material obtained waspurified by preparative TLC to afford compound INT-50 (6.0 mg, 40%) as ayellow solid. ¹H NMR (400 MHz. DMSO-d₆): δ 2.25 (s, 3H), 2.52-2.54 (m,2H), 3.22-3.25 (m, 1H), 3.32-3.35 (m, 1H), 3.55-3.60 (m, 1H), 7.14 (t,J=5.6 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.19 (d,J=8.8 Hz, 1H), 8.23 (br s, 1H), 9.24 (d, J=9.2 Hz, 1H). MS m/z (M+H):347.1.

Synthesis of(R)-6-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinamide(INT-1)

The title compound was synthesized in the same manner as I-1substituting 4-amino-6-chloro-N-(4-methoxybenzyl)nicotinamide for5-fluoro-2-nitroaniline. Heating was done conventionally at 100° C. for3 h (rather than by microwave irradiation) to afford compound INT-51 (15mg, 47% yield) as yellow solid. MS: m/z 573.2 (M+H).

Synthesis of(S)₂-chloro-4-((10-(hydroxymethyl)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)-N-(4-methoxybenzyl)pyrimidine-5-carboxamide(INT-52)

The title compound was synthesized in the same manner as I-17substituting4-amino-2-chloro-N-(4-methoxybenzyl)pyrimidine-5-carboxamide for6-fluoropyrimidin-4-amine to afford compound INT-52 (22 mg, 14%) as apale yellow solid. MS m/z (M+H): 590.3.

Synthesis of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (59-1)

To a mixture of 1H-pyrimidine-2,4-dione (20 g, 178.4 mmol) in aqueoussolution of potassium hydroxide (8.0 g, 142.7 mmol) in water (160.0 mL),paraformaldehyde (6.96 g, 231.9 mmol) was added portion-wise at 0° C.The resulting reaction mixture was stirred at 55° C. for 36 h. Aftercompletion, the reaction was cooled to room temperature and concentratedto ⅓^(rd) of the volume under reduced pressure to yield a white thickmass. The residue was diluted with acetone (150 mL) and stirred at 25°C. for 15 min at which point a precipitate formed. The solid wasfiltered and washed with acetone (3×50 mL) and dried under vacuum toafford S9-1 (25 g, 98%) as a white solid. MS m/z (M−H): 140.9.

Synthesis of 2,4-Dichloro-5-(chloromethyl)pyrimidine (S9-2)

To a suspension of S9-1 (25 g, 175.9 mmol) in toluene (50.0 mL),phosphorus oxychloride (134.87 g, 879.6 mmol) was added at 0° C., andstirring was continued for 15 min. To the reaction mixture, DIPEA (68.1g, 527.7 mmol) was added dropwise while maintaining the temperature at0° C. The resulting reaction mixture was stirred at 120° C. for 7 h.After completion of the reaction, the reaction mixture was cooled toroom temperature and poured into a stirred bi-phasic mixture of ethylacetate and water (150 mL/150 mL) at 0° C. over a period of 45 min andstirred at same temperature for another 1.5 h. The reaction mixture wasthen extracted with 25% ethyl acetate in toluene (4×150 mL). Thecombined organic layer was washed with water (2×500 mL) and saturatedbrine solution (1×500 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford 59-2(28 g, 81%) as a brown liquid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 4.84 (s, 2H).

Synthesis of 2,4-Dichloro-5-(iodomethyl)pyrimidine (INT-53)

To a solution of sodium iodide (23.4 g, 156.0 mmol) in dry acetone (150mL), S9-2 (28.0 g, 141.8 mmol) was added at mom temperature and stirredfor 30 min. The resulting reaction mixture was warmed to 65° C. for 20min. After completion, the reaction mixture was cooled to roomtemperature, filtered and washed with acetone (2×50 mL). The combinedfiltrate was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material obtained was purified by flashcolumn chromatography (silica gel 60-120, 10% acetone in Pet. ether) toafford INT-53 (21 g, 48%) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.95 (s, 1H), 4.53 (s, 2H). MS m/z (M+H): 287.9.

Synthesis of 2,4-dichloro-5-((methylsfonyl)methyl)pyrimidine (INT-54)

INT-53 (0.3 g, 1.038 mmol) was dissolved in 10 mL DCM with 2 mL DMSO.Sodium methanesulfinate (0.106 g, 1.038 mmol) was added and the reactionwas warmed to 50° C. After 3 h the reaction was diluted with heptane,filtered and concentrated to give INT-54 in DMSO which was used directlyfor the next step. MS m/z (M+H): 241.0, 243.0.

Synthesis of 2,4-dichloro-5-((difluoromethoxy)methyl)pyrimidine (INT-55)

To a stirred solution of (2,4-dichloropyrimidin-5-yl)methanol (400 mg,2.23 mmol) in CH₃CN (16 mL) was added copper(I) iodide (45.6 mg, 0.24mmol) at room temperature under inert atmosphere followed by stirring at60° C. for 10 min. 2,2-Difluoro-2-(fluorosulfonyl) acetic acid (2.39 g,14.4 mmol) was added dropwise and the reaction mixture was maintained at60° C. for another 4 h. The reaction mixture was quenched by addition ofice-cold water (30 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to obtain thecrude material. Purification by column chromatography on silica gel(eluent: 15% EtOAc/Hexanes) to afford compound INT-55 (200 mg, 0.55mmol, 24.5%) as a colorless oil. MS m/z (M+H): 229.0.

Synthesis of 5-(tert-butoxymethyl)-2,4-dichloropyrimidine (INT-56)

To a stirred solution of (2,4-dichloropyrimidin-5-yl)methanol (200 mg,1.12 mmol) in a mixture of DCM (2 mL) and cyclohexane (2 mL) was addedtert-butyl 2,2,2-trichloroethanimidate (268.56 mg, 1.23 mmol) and BF₃Et₂O (50 uL) at room temperature. The reaction was stirred at roomtemperature for 15 h. The crude product was purified by preparative-TLC(hexane/ethyl acetate, 5:1) to obtain INT-56 (200 mg, 76.1%) as anoff-white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 4.52 (s, 2H),1.33 (s, 9H).

Synthesis of 5-(bromomethyl)-4-chloropyrimidine (INT-57)

To a stirred solution of 4-chloro-5-methyl-pyrimidine (1.2 g, 9.33 mmol)in CCl₄ (30 mL) was added 1-bromopyrrolidine-2,5-dione (2.66 g, 14.9mmol) and AIBN (0.31 g, 1.87 mmol) at room temperature and was stirredat 80° C. for 4 h. The reaction was quenched by addition of saturatedaqueous Na₂SO₃ (40 mL). The organic layer was separated and the aqueouslayer was extracted with dichloromethane (2×30 mL). The combined organiclayer was washed with brine (100 mL), filtered and concentrated underreduced pressure to give the crude material. Purification by columnchromatography (petroleum ether:ethyl acetate=10:1) afforded INT-57 (500mg, 25.8%) as a colorless oil.

Synthesis ofN-((4-chloropyrimidin-5-yl)methyl)-N,2-dimethylpropan-2-amine (INT-58)

To a stirred solution of 5-(bromomethyl)-4-chloro-pyrimidine (300.0 mg,1.45 mmol) in MeCN (20 mL) was added N,2-dimethylpropan-2-amine (113.4mg, 1.3 mmol) and K₂CO₃ (393.3 mg, 2.9 mmol) at 0° C. and was stirred atthis temperature for 1.5 h. The reaction mixture was filtered through apad of Celite® and the filtrate was concentrated under reduced pressureto give the crude material. Purification by column chromatography(petroleum ether:ethyl acetate=15:1) afforded INT-58 (140 mg, 45.3%) asa colorless oil.

5-(Allyloxymethyl)-2,4-dichloro-pyrimidine (INT-59)

To a solution of allyl alcohol (0.08 mL, 1.25 mmol) in tetrahydrofuran(3.0 mL), potassium tert-butoxide (174.8 mg, 1.56 mmol) was added at 0°C. and stirred for 30 min followed by the addition of INT-53 (300 mg,1.0 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C.for 15 min. After completion, ice water (5.0 mL) was added to thereaction mixture and it was then extracted with ethyl acetate (10.0 mL).The organic layer was washed with water (10.0 mL) followed by saturatedbrine solution (10.0 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain a cruderesidue (300 mg). The residue was purified by preparative TLC to affordINT-59 (50 mg, 10%) as a brown liquid. MS m/z (M+H): 219.1

2,4-Dichloro-5-(ethoxymethyl)pyrimidine (INT-60): Method A

A solution of sodium hydride (or KOtBu, 8.3 mmol) (199.4 mg, 8.3 mmol)in ethanol (15.0 mL) was stirred at 50° C. for 45 min. To the mixture,INT-53 (3.0 g, 10.4 mmol) was added at 0° C. The resulting reactionmixture was stirred at room temperature for 10 min. After completion,the reaction mixture was diluted with ice cold water (50.0 mL),extracted with ethyl acetate (2×100 mL) and washed with brine solution(50 mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure (2.8 g). The crude material obtainedwas purified by preparative TLC to afford INT-60 (402 mg, 19%) as acolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 4.56 (s, 2H),3.69-3.64 ((m, 2H), 1.30 (t, J=7.2 Hz, 3H). MS m/z (M+H): 207.1.

Alternative Synthesis of 2,4-Dichloro-5-(ethoxymethyl)pyrimidine(INT-60): Method B

To a solution of ethanol (20 mL) was added acetyl chloride (0.55 g, 7.04mmol). The mixture was stirred at room temperature for 10 min then S9-1(1.0 g, 7.04 mmol) was added. The mixture was warmed to 75-80° C.overnight, cooled and then concentrated to afford crude5-(ethoxymethyl)pyrimidine-2,4(1H,3H)-done (1.15 g, 96%) as a whitesolid, which was used for the next step without further purification.

To a suspension of 5-(ethoxymethyl)pyrimidine-2,4(1H,3H)-dione (0.5 g,2.94 mmol) in toluene (1 mL), phosphorus oxychloride (0.67, 7.35 mmol)was added at 0° C., and stirred for 15 min. To the reaction mixture,Hünig's base (0.77 mL, 4.41 mmol) was added dropwise at 0° C. Theresulting reaction mixture was stirred at 120° C. for 1 h then cooled toroom temperature and poured into a stirring biphasic mixture of ethylacetate and water (1/1, v/v) at 0° C. over a period of 45 min. Stirringwas continued at the same temperature for an additional 1.5 h. Thereaction mixture was then extracted with ethyl acetate. The combinedorganic layer was washed with water and brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford INT-60(0.40 g, 65%) as a brown liquid. The crude product was further purifiedby silica gel chromatography (petroleum ether/ethyl acetate, 30/1 to20/1). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 4.56 (s, 2H), 3.66 (q,J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

Method C:

To a suspension of NaH (79.75 mg, 3.32 mmol) in anhydrous THF (50 mL) at0° C. under nitrogen atmosphere was added 3-methyloxetan-3-ol (268.39mg, 3.05 mmol). After stirring for 30 min at 0° C., the reaction mixturewas transferred via cannula to a solution of INT-53 (800 mg, 2.77 mmol)in anhydrous THF (50 mL). After stirring for an additional 2 h at 0° C.,NH₄Cl (satd. aq) was added and the reaction was extracted with ethylacetate (3×50 mL). The combined organic extracts were dried over MgSO₄,concentrated under reduced pressure and the resulting residue waspurified by silica column chromatography eluting with a mixture ofpetroleum ether:ethyl acetate (1/1). INT-61 (350 mg, 51%) was obtainedas a brown solid. ¹H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 4.77-4.75 (d,J=6.8 Hz, 2H), 4.53 (s, 2H), 4.48-4.46 (d, J=7.2 Hz, 2H), 1.66 (s, 3H).MS m/z (M+H): 249.1.

The following intermediates were synthesized by one or more of Method A,Method B, or Method C as described above, by replacing the ethanol or3-methyloxetan-3-ol of those methods with the respective alcohol in thecolumn labeled “Alcohol” to give the compounds shown in the “product”column of the table below.

Methods A and C

Method B

Alcohol Product MS NMR Method 2,2-difluoroethan-1-ol

INT-62 ¹H NMR (300 MHz, CDCl₃): δ 8,66 (s, 1H), 6.16-5.77 (m, 1H), 4.71(s, 2H), 3.91-3.81 (m, 2H). MS m/z (M + H): 242. C methanol

INT-63 ¹H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 4.54 (s, 2H), 3.53 (s,3H). A 2-methoxyethan-1-ol

INT-64 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (s, 1H), 4.65 (s, 2H), 3.78-3.76(m, 2H), 3.64-3.61 (m, 2H), 3.41 (s, 3H). C 2-fluoroethan-1-ol

INT-65 ¹H NMR (400 MHz, CDCl₃): δ 8.68 (s, 1H), 4.57 (t, J = 4.8 Hz,1H), 4.52 (t, J = 4.8 Hz, 1H), 3.70 (s, 2H), 2.86 (t, J = 4.8 Hz, 1H),2.78 (t, J = 4.8 Hz, 1H). B or C (S)-tetrahydrofuran-3- ol

INT-66 MS m/z (M + H): 249.1. ¹H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H),4.62 (s, 2H), 4.32-4.30 (m, 1H), 4.03-3.84 (m, 4H), 2.17-2.11 (m, 2H). Ctetrahydro-2H-pyran- 4-ol

INT-67 ¹H NMR (300 MHz, CDCl₃) δ 8.69 (s, 1H), 4.61 (s, 2H), 4.01-3.94(m, 2H), 3.73-3.65 (m, 1H), 3.53-3.45 (m, 2H), 2.02-1.96 (m, 2H), 1.75-1.67 (m, 2H). C 3-hydroxy propanenitrile

INT-68 MS m/z (M + H): 231.9 C

Synthesis ofrac-2,4-dichloro-5-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)pyrimidine

To a stirred suspension of INT-53 (500.0 mg, 1.73 mmol) in anhydrousCH₃CN (20 mL, DMF is also an acceptable solvent for this transformation)was added potassium carbonate (358.3 mg, 2.6 mmol) andrac-2-(methoxymethyl)pyrrolidine hydrochloride (262.4 mg, 1.73 mmol) at0° C. to give a brown solution. The solution was stirred for 3 h. Thereaction mixture was diluted with chloroform and concentrated.Purification by preparative TLC (hexane:ethyl acetate 3/1) affordedINT-69 (160 mg, 33.4%) MS m/z (M+H): 276.2.

The following intermediates were synthesized by the same method asINT-69 by replacing rac-2-(methoxymethyl)pyrrolidine hydrochloride withthe respective amine in the column labeled “Amine” using the procedureabove to give the compounds shown in the product column.

Amine Product MS NMR N-methylpropan-2-amine

INT-70 MS m/z (M + H): 234.0. ¹H-NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H),3.59-3.52 (m, 2H), 2.99- 2.91 (m, 1H), 2.36-2.31 (m, 3H), 1.25 (s, 3H),1.22-1.09 (m, 6H). 3-isopropoxyazetidine

INT-71 MS m/z (M + H): 275.9 N-methylcyclohexanamine

INT-72 MS m/z (M + H): 274.0 4-methoxypiperidine

INT-73 ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 3.58 (s, 2H), 3.34 (s,3H), 3.29-3.26 (m, 1H), 2.73- 2.71 (m, 2H), 2.34-2.26 (m, 2H), 1.94-1.86(m, 1H), 1.66-1.60 (m, 1H). 1-ethylpiperazine

INT-74 ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 3.62 (s, 2H), 2.67-2.53(m, 10H), 1.18 (t, J = 6.0 Hz, 3H). 3-azabicyclo[3.1.0]hexane

INT-75 MS m/z (M + H): 244.0 3-azabicyclo[3.1.1]heptane

INT-76 MS m/z (M + H): 258.0 ¹H-NMR (400 MHz, CDCl₃-d₁): δ 8.61 (s, 1H),3.77 (s, 2H), 2.91 (s, 4H), 2.35-2.34 (m, 2H), 2.04-2.02 (m, 2H), 1.55-1.53 (m, 2H). diisobutylamine

INT-77 MS m/z (M + H): 289.6 rac-2- (methoxymethyl)pyrrolidine

INT-78 MS m/z (M + H): 276.2 2-methoxy-N-methylethan- 1-amine

INT-79 ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 3.69 (s, 2H), 3.54 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 2.70 (t, J = 5.4 Hz, 2H), 2.36 (s, 3H).3,3-dimethylpiperidine

INT-80 MS m/z (M + H): 273.9 (R)-2-methylpyrrolidine

INT-81 MS m/z (M + H): 246.1 (S)-2-methylpyrrolidine

INT-82 MS m/z (M + H): 246.1 3-oxa-8- azabicyclo[3.2.1]octane

INT-83 MS m/z (M + H): 274.1 ¹H NMR (300 MHz, CDCl₃) δ 8.89 (s, 1H),3.77-3.74 (m, 2H), 3.57- 3.51 (m, 4H), 3.02 (s, 2H), 2.05-2.01 (m, 4H).tert-butyl (2S,6R)-2,6- dimethylpiperazine-1- carboxylate

INT-84 MS m/z (M + H): 375.0 (S)-3-methoxypiperidine

INT-85 MS m/z (M + H): 275.9 (R)-3-methoxypiperidine

INT-86 MS m/z (M + H): 275.9 2-ethoxy-N-methylethan-1- amine

INT-87 MS m/z (M + H): 263.6 2-methylpropan-2-amine

INT-88 MS m/z (M + H): 234.1 diisopropylamine

INT-89 MS m/z (M + H): 262.1 ¹H NMR (400 MHz, CDCl3): δ 8.55 (s, 1 H),3.21 (s, 2 H), 2.53 (m, 2H), 0.64 (d, J = 10.1 Hz, 12H)N,2-dimethylpropan-2- amine

INT-90 MS m/z (M + H): 248.1 piperidin-4-ol

INT-97 4-ethoxypiperidine HCl

INT-98

Synthesis of (R)-methyl2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidine-4-carboxylate(INT-91)

INT-6 (0.3 g, 1.002 mmol) was added to 15 mL of dry DMF and sonicated.To the resulting solution, K₂CO₃ (1.385 g, 10.02 mmol) was added and thereaction was warmed to 90° C. for 10 min. The reaction was then cooledand methyl 2,6-dichloropyrimidine-4-carboxylate (0.270 g, 1.303 mmol)was added. The reaction was flushed with argon and warmed again at 90°C. for 3h. Once the reaction was judged complete, the reaction wascooled, filtered and poured into water. The yellow precipitate thatdeveloped was isolated by filtration, triturated with EtOAc and driedunder vacuum overnight. The resulting powder, INT-91 (0.373 g, 0.794mmol, 79% yield) was used without further purification for subsequenttransformations. MS m/z (M+H): 470.0.

Synthesis of(R)-3-((2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-92)

INT-91 (0.373 g, 0.794 mmol) was dissolved in DCM (6 mL) with MeOH (1.2mL) and cooled to 0° C. Sodium borohydride (0.120 g, 3.18 mmol) wasadded in two portions over the course of 30 min. The reaction wasallowed to stir for two hours upon which time it was diluted with 5 mLof methanol and was concentrated onto silica gel. It was then purifiedby flash chromatography using a gradient of 0-10% MeOH in DCM to yieldINT-92 (0.141 g, 0.319 mmol, 40.2% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 9.35 (d, J=9.2 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.14(d, J=5.2 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.25(s, 1H), 7.15 (br, 1H), 4.56 (s, 2H), 3.59 (m, 1H), 3.44 (m, 2H), 1.16(d, J=6.4 Hz, 3H). MS m/z (M+H): 442.1.

Synthesis of(R)-3-((2-chloro-6-(chloromethyl)pyrmidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-93)

In a 20 mL vial, CCl₄ (0.277 ml, 2.87 mmol) and triphenylphosphine (753mg, 2.87 mmol) were stirred at room temperature in 5 mL DCM for 15 min.The aforementioned solution was then transferred into a vial containingINT-92 (141 mg, 0.319 mmol). 2 mL of dry DMF were added to aid insolubilizing the starting material and the reaction was warmed to 50° C.overnight. The next morning the reaction was judged to be complete,concentrated onto silica gel and purified by flash chromatography usinga gradient of 0-10% MeOH in DCM to yield INT-93 (137 mg, 0.298 mmol, 93%yield). MS m/z (M+H): 460.0; 462.0.

Synthesis of (R)-tert-butyl4-(2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(INT-94)

I-116 (240 mg, 0.489 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(227 mg, 0.734 mmol), potassium carbonate (203 mg, 1.467 mmol), andPdCl₂(dppf) (35.8 mg, 0.049 mmol) in DMF (8.0 mL) were degassed byevacuation/sonication (3×), backfilling each time with N₂. The reactionmixture was heated at 85° C. with stirring. After 3h, the mixture wasdiluted with water and extracted with DCM (5×). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. Purification by HPLC (10-95% MeCN/Water, 0.1% TFA) gaveINT-94 (54 mg, 0.091 mmol, 19% yield) as a yellow solid.

Synthesis of(R)-3-((2-chloro-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-95)

INT-94 (54 mg, 0.091 mmol) was dissolved in TFA (1.0 mL) to give redsolution. After 3 min, UPLC shows complete reaction. TFA was removed byrotary evaporation, and the resulting dark red residue was treated withammonium hydroxide (˜2 mL, carefully, dropwise). Color changed from darkred to yellow, and a precipitate formed. The mixture was sonicated toform a suspension which was concentrated by rotary evaporation to give ayellow solid residue that was used directly without furtherpurification.

Synthesis of(R)-3-((((allyloxy)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-96)

To a solution of INT-6 (50 mg, 0.2 mmol) in dimethylformamide (1.0 mL),potassium tert-butoxide (37.2 mg, 0.3 mmol) was added at 0° C. andstirred for 10 min followed by the addition of INT-59 (72.7 mg, 0.3mmol) at 0° C. The resulting reaction mixture was stirred at roomtemperature for 1 h. After completion, the reaction mixture was quenchedwith water (5.0 mil) and extracted with 10% methanol/dichloromethane(2×10 mL). The organic layer was washed with water (10 mL) followed bysaturated brine solution (10 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude material obtained (50 mg) was purified by preparative TLC toafford INT-96 (5 mg, 6%) as a pale yellow solid. MS m/z (M+H): 482.1.

Synthesis of2,4-dichloro-5-((4-(2-methoxyethoxy)piperidin-1-yl)methyl)pyrimidine(INT-99)

To a stirred suspension of K₂CO₃ (539.0 mg, 3.9 mmol) and INT-53 (750mg, 2.6 mmol) in CH₃CN (25.0 mL) was added 4-(2-methoxyethoxy)piperidinehydrochloride (250.0 mg, 1.3 mmol) at 0° C. The resulting reactionmixture was stirred at room temperature for 2 h. After completion, thereaction mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford INT-99 (152.0 mg, 36.5%) asa colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 3.62-3.53(m, 6H), 3.45-3.37 (m, 4H), 2.85-2.72 (m, 2H), 2.35-2.22 (m, 2H),2.00-1.82 (m, 2H), 1.72-1.55 (m, 2H). MS m/z (M+H): 320.1.

Synthesis of 2,4-dichloro-5-((4-(2-fluoroethoxy)piperidin-1-yl)methyl)(INT-100)

To a stirred suspension of K₂CO₃ (602.0 mg, 4.4 mmol) and INT-53 (1.6 g,5.5 mmol) in CH₃CN (25.0 mL) was added 2-(piperidin-4-yloxy)ethanolhydrochloride (604.0 mg, 2.2 mmol) at 0° C. The resulting reactionmixture was stirred at room temperature for 2 h. After completion, thereaction mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford2-((1-((2,4-dichloropyrimidin-5-yl)methyl)piperidin-4-yl)oxy)ethan-1-ol(304.0 mg, 45%) as a colorless liquid. MS m/z (M+H): 302.1.

To a stirred solution of2-((1-((2,4-dichloropyrimidin-5-yl)methyl)piperidin-4-yl)oxy)ethan-1-ol(304.0 mg, 1.0 mmol) in CH₂Cl₂ (8.0 mL) was added DAST (322.0 mg, 2.0mmol) at 0° C. The resulting reaction mixture was stirred at roomtemperature for 2 h. After completion, the reaction mixture wasconcentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford INT-100 (70.0 mg, 23%) as acolorless liquid. MS m/z (M+H): 308.2.

Synthesis of2,4-dichloro-5-((4-(methoxy-d3)piperidin-1-yl)methyl)pyrimidine(INT-101)

To a stirred suspension of K₂CO₃ (539.0 mg, 3.9 mmol) and INT-53 (750mg, 2.6 mmol) in CH₃CN (25.0 mL) was added 4-(methoxy-d3)piperidinehydrochloride (250.0 mg, 1.3 mmol) at 0° C. The resulting reactionmixture was stirred at room temperature for 2 h. After completion, thereaction mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford INT-101 (167.0 mg, 46%) as acolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 3.57 (s, 2H),3.31-3.20 (m, 1H), 2.78-2.65 (m, 2H), 2.38-2.22 (m, 2H), 1.95-1.82 (m,2H), 1.70-1.54 (m, 2H). MS m/z (M+H): 279.1.

Synthesis of2,4-dichloro-5-((4-isopropoxypiperidin-1-yl)methyl)pyrimidine (INT-102)

To a stirred suspension of K₂CO₃ (1.45 g, 10.5 mmol) and INT-53 (2.0 g,6.9 mmol) in CH₃CN (50 mL) was added 4-isopropoxypiperidinehydrochloride (623 mg, 3.5 mmol) at 0° C. portionwise. The resultingreaction mixture was stirred at room temperature for 2 h. Aftercompletion, the reaction mixture was filtered through a pad of Celite®and the filtrate was concentrated under reduced pressure. The crudematerial obtained was purified by column chromatography to affordINT-102 (547 mg, 51.5%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ8.66 (s, 1H), 3.72-3.66 (m, 1H), 3.61-3.54 (m, 2H), 3.47-3.38 (m, 1H),2.81-2.69 (m, 2H), 2.35-2.22 (m, 2H), 1.93-1.79 (m, 2H), 1.68-1.54 (m,2H), 1.14 (d, J=4.0 Hz, 6H). MS m/z (M+H): 304.2.

Synthesis of5-((4-(tert-butoxy)piperidin-1-yl)methyl)-2,4-dichloropyrimidine(INT-103)

To a stirred suspension of K₂CO₃ (478.0 mg, 3.5 mmol) and INT-53 (500.0mg, 1.7 mmol) in CH₃CN (15.0 mL) was added 4-tert-butoxypiperidinehydrochloride (200.0 mg, 1.0 mmol) at 0° C. The resulting reactionmixture was stirred at room temperature overnight. After completion, thereaction mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure. The crude material obtained waspurified by column chromatography to afford INT-103 (168 mg, 53%) as acolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 3.58 (s, 2H),3.53-3.47 (m, 1H), 2.80-2.76 (m, 2H), 2.35-2.20 (m, 2H), 1.83-1.69 (m,2H), 1.66-1.54 (m, 2H), 1.20 (s, 9H). MS m/z (M+H): 318.0.

Synthesis of 2,4-dichloro-5-((ethoxy-d₅)methyl)pyrimidine (INT-104)

Sodium ethan-1-olate-d₅ (0.969 mmol) in 3.0 mL THF was prepared asfollows. To a suspension of sodium hydride (60% in mineral oil, 44.3 mg,1.108 mmol) in THF (3.0 mL) at 0° C. was added ethan-1,1,2,2,2-d₅-1-ol-d(0.057 mL, 0.969 mmol). The cooling bath was removed and the resultingmixture was stirred at room temperature for 40 min.

A first portion of sodium ethan-1-olate-d in THF (3.0 mL; 0.969 mmol)was prepared according to the above procedure and cooled to 0° C. To thecooled solution of sodium ethan-1-olate-d₅ in THF was added a solutionof INT-53 (400 mg, 1.385 mmol) in THF (3.0 mL). After 2 h, a secondportion of sodium ethan-1-olate-d₅ in THF (3.0 mL; 0.969 mmol) wasprepared according to the above procedure, cooled to 0° C. and added tothe reaction mixture. After 14 h, the reaction mixture was diluted withsaturated ammonium chloride solution (5.0 mL), extracted with ethylacetate (2×20 mL) and washed with brine solution (5 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material obtained was purified by flashchromatography on a silica gel column eluting with 5% to 20%EtOAc-Heptane gradient to afford INT-104 (99 mg, 34% yield) as acolorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 4.53 (s,2H). MS m/z (M+H): 212.1.

Example 1

Synthesis of (R)-ethyl2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxylate(I-18)

In a 20 mL vial,(R)-3-amino-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-3) (0.095 g, 0.318 mmol), ethyl2,4-dichloropyrimidine-5-carboxylate (0.084 g, 0.382 mmol), and Hünig'sBase (0.111 ml, 0.637 mmol) were added to 5 mL of i-PrOH. The vial wassealed and the suspension warmed to 95° C. for 24 hours. Once determinedto be complete, the reaction was cooled and a precipitate formed. 5 mLof ethyl ether was added, the vial was sonicated briefly, and theproduct was isolated by filtration to afford compound I-18 (0.112 g,0.232 mmol, 72.8% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7Hz, 3H), 1.35 (t, J=7 Hz, 3H), 3.42-3.46 (m, 2H), 3.60 (m, 1H), 4.39 (q,J=7 Hz, 2H), 7.08 (br s, 1H), 7.81 (d, J=9.0 Hz, 1H), 8.06 (d, J=4 Hz,1H), 8.10 (d, J=9.0 Hz, 1H), 8.54 (d, J=9.2 Hz, 1H), 8.93 (s, 1H), 9.27(d, J=9.3 Hz, 1H), 10.99 (s, 1H). MS m/z (M+H): 483.29.

Example 2

Synthesis of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carbonitrile(I-16)

The title compound was synthesized in the same manner as I-18substituting 2,4-dichloropyrimidine-5-carbonitrile in place of ethyl2,4-dichloropyrimidine-S-carboxylate to afford compound I-16 (13 mg, 11%yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.17 (d, J=6.5 Hz,3H), 3.40-3.44 (m, 2H), 3.56-3.60 (m, 1H), 7.08 (hr s, 1H), 7.84 (d,J=8.8 Hz, 1H), 7.89 (s, 1H), 8.09 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.81(hr s, 1H), 9.20 (d, J=9.4 Hz, 1H), 11.14 (s, 1H). MS m/z (M+H): 436.27.

Example 3

Synthesis of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino-[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)-N-(1-methylpiperidin-4-yl)pyrimidine-5-carboxamide(I-19)

In a 4 dram vial, DMF (0.5 mL) was added to the mixture of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxylicacid (INT-41) (10 mg, 0.022 mmol) and HATU (9.19 mg, 0.024 mmol). Theresulting mixture was cooled to 0° C. using an ice-methanol coolingbath. Then, pre-mixed 1-methylpiperidin-4-amine (2.51 mg, 0.022 mmol)and DIPEA (0.012 mL, 0.066 mmol) in 0.5 ml of DMF (0.5 mL) were addedslowly to the above mixture, and the reaction was stirred while warmingto room temperature for 30 minutes. After completion of the reaction,the crude mixture was purified on preparative-HPLC usingacetonitrile/H₂O (01% TFA) to afford compound I-19 (4 mg, 7.26 μmol,33.0% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.20-9.04 (m, 3H),8.38-8.09 (m, 4H), 7.40 (d, 1H), 7.13 (br s, 1H), 3.52-3.36 (m, 4H),3.05-3.01 (m, 2H), 2.73 (m, 3H), 2.17-1.71 (m, 4H), 1.17 (d, 3H). MSm/z: 514.9 (M−36⁺).

Example 4

Synthesis of(R)-2-chloro-N-cyclopropyl-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(I-21)

The title compound was synthesized in the same manner as I-19 usingcycloproylamine in place of 1-methylpiperidin-4-amine to afford compoundI-21 as a solid. MS m/z: 457.9 (M−36).

Example 5

Synthesis of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide(I-20)

The title compound was synthesized in the same manner as I-19 usingoxetan-3-amine in place of 1-methylpiperidin-4-amine to afford compoundI-20, isolated as a solid. MS m/z: 473.9 (M−36).

Example 6

Synthesis of(R)-3-((2-chloro-5-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-24)

The title compound was synthesized in the same manner as I-19 using(R)—N,N-dimethylpyrrolidin-3-amine in place of 1-methylpiperidin-4-amineto afford compound I-24, isolated as a solid. ¹H NMR (400 MHz, DMSO-d6):δ 9.90 (br s, 1H), 9.24 (d, 1H), 9.20 (d, 1H), 9.04 (d, 1H), 8.20 (m1H), 8.19 (d, 1H), 7.34 (m, 1H), 7.11 (br t, 1H), 4.07-3.30 (m, 5H,partially overlapped by water), 2.87 (br s, 6H), 2.49-2.15 (m, 2H,partially merged with solvents peak), 1.17 (d, 3H).

Example 7

Synthesis of(R)-6-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinonitrile(I-25)

To a solution of(R)-3-amino-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-3) (60 mg, 0.2 mmol) in 1,4-dioxane (3.0 mL),6-chloro-4-iodonicotinonitrile (63.8 mg, 0.2 mmol) and potassiumcarbonate (55.6 mg, 0.4 mmol) were added at room temperature. Thereaction mixture was degassed for 5 minutes followed by the addition ofPd₂(dba)₃ (9.1 mg, 0.01 mmol) and Xantphos (19.2 mg, 0.03 mmol) at roomtemperature. The resulting reaction mixture was stirred at 100° C. for 8h. After completion, the reaction mixture was concentrated under reducedpressure. The residue obtained was diluted with water (7.0 mL), leadingto the formation of a solid precipitate. The solids were filtered andair dried, then crystallized from dimethylsulfoxide/water to affordcompound I-25 (40 mg, 43%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.19 (d, J=6.6 Hz, 3H), 3.45 (br s, 2H), 3.59 (br s, 1H), 7.01 (br s,1H), 7.64 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 8.03-8.08 (m, 2H),8.68 (s, 1H), 8.83 (s, 1H), 9.13 (d, J=9.3 Hz, 1H), 10.1 (br s, 1H). MSm/z (M+H): 435.2.

Example 8

Synthesis of(R)-6-fluoro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinonitrile(I-27)

The title compound was synthesized in the same manner as I-25,substituting 6-fluoro-4-iodonicotinonitrile for6-chloro-4-iodonicotinonitrile to afford compound I-27 (40 mg, 28%),isolated as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (d, J=6.7Hz, 3H), 3.45 (br s, 2H), 3.55 (br s, 1H), 7.01 (br s, 1H), 7.67 (d,J=9.1 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 8.03-8.07 (m, 2H), 8.51 (s, 1H),8.61 (s, 1H), 9.14 (d, J=9.0 Hz, 1H), 10.1 (br s, 1H). MS m/z (M+H):419.3.

Example 9

Synthesis of(R)-6-fluoro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinamide(I-29)

(R)-6-Fluoro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinonitrile(I-27) (30 mg, 0.1 mmol) was treated with conc. H₂SO₄ (0.5 mL) at 0° C.The resulting reaction mixture was stirred at 60° C. for 1 h. Aftercompletion of the reaction, the reaction mixture was quenched with coldwater (1.0 mL), whereupon solids formed. The obtained solids werefiltered and air dried to obtain the crude product. The crude productwas dissolved in dimethyl sulfoxide (1.0 mL) and warmed to 80° C. thenfiltered to remove un-dissolved particles. To the filtrate, water (1.0mL) was added. The solids formed were filtered and air dried to affordcompound I-29 (6.0 mg, 17%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.19 (d, J=6.7 Hz, 3H), 3.44 (br s, 2H), 3.58-3.59 (m, 1H),7.01 (br s, 1H), 728 (d, J=6.7 Hz, 1H), 7.85 (br s, 1H), 7.88 (d, J=8.8Hz. 1H), 8.02 (br s, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.42 (br s, 1H), 8.63(s, 1H), 8.85 (s, 1H), 9.11 (d, J=8.9 Hz, 1H), 12.08 (s, 1H). MS m/z(M+H): 437.2.

Example 10

Synthesis of(R)-10-methyl-3-((2-(methylsulfonyl)pyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-14)

To a solution of (R)-tert-butyl10-methyl-3-((2-(methylsulfonyl)pyrimidin-4-yl)amino)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-12(9H)-carboxylate(INT-42) (15.0 mg, 0.03 mmol) in dichloromethane (2.0 mL),trifluoroacetic acid (2.0 mL) was added at 0° C. The resulting reactionmixture was allowed to stir at 0° C. for 20 min. After completion of thereaction, the reaction mixture was concentrated under reduced pressureand azeotroped with chloroform (2×10 mL). The residue obtained wasdiluted with saturated sodium bicarbonate solution (10 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by preparative TLC to affordcompound I-14 (6.0 mg, 49%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.18 (d, J=6.7 Hz, 3H), 3.39 (s, 3H), 3.45 (br s, 2H), 3.59(br s, 1H), 7.02 (br s, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.93 (br s, 1H),8.03 (d, J=4.1 Hz, 1H), 8.45 (br s, 1H), 8.09 (d, J=8.9 Hz, 1H), 8.70(d, J=5.9 Hz, 1H), 9.15 (d, J=9.3 Hz, 1H), 11.19 (br s, 1H). MS: m/z455.3 (M+H).

Example 11

Synthesis of(R)-3-((5-fluoro-2-nitrophenyl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-1)

(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (120 mg, 0.4 mmol) in 1,4-dioxane (5 mL) was treated with5-fluoro-2-nitroaniline (70 mg, 0.4 mmol). The resulting solution wasbriefly degassed by applying vacuum and then flushed with nitrogen.Cesium carbonate (246 mg, 0.7 mmol), Pd₂(dba)₃ (17 mg, 0.01 mmol) andXantphos (43 mg, 0.07 mmol) were added, and the mixture was furtherdegassed as described above. The reaction mixture was stirred undermicrowave irradiation at 130° C. for 1 h. After completion of thereaction, the reaction mixture was filtered through celite, washed withethyl acetate and concentrated under reduced pressure. The resultingresidue was triturated with diethyl ether and further purified bypreparative HPLC to afford compound I-1 (16 mg, 10%) as a pale brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7 Hz, 3H), 3.44 (br s,2H), 3.58 (br s, 1H), 7.00-7.04 (m, 2H), 7.47 (d, J=9.1 Hz, 1H), 7.73(d, J=8.9 Hz, 1H), 8.01-8.03 (m, 2H), 8.24 (dd, J=6.1, 9.2 Hz, 1H), 8.73(dd, J=2.6, 12.1 Hz, 1H), 9.07 (d, J=9.1 Hz, 1H), 10.26 (s, 1H). MS: m/z(M+H): 438.22 (M+H).

Example 12

Synthesis of(R)-4-fluoro-2-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)benzonitrile(I-2)

The title compound was synthesized in the same manner as I-1substituting 2-amino-4-fluoro benzonitrile for 5-fluoro-2-nitroanilineto afford compound I-2, obtained as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ: 1.18 (d, J=6.7 Hz, 3H), 3.44 (s, 2H), 3.57-3.59 (m, 1H),6.97 (t, J=5 Hz, 1H), 7.03 (dt, J=2.5, 8.4 Hz, 1H), 7.45 (d, J=9 Hz,1H), 7.70 (d, J=9 Hz, 1H), 7.86 (dd, J=6.4, 8.7 Hz, 1H), 7.98 (d, J=8.8Hz, 1H), 8.02 (d, J=4.3 Hz, 1H), 8.35 (dd, J=2.5, 12 Hz, 1H), 9.03 (d,J=9 Hz, 1H), 9.61 (s, 1H). MS: m/z 418.1 (M+H).

Example 13

Synthesis of(R)-3-((2-chloropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-5)

The title compound was synthesized in the same manner as I-1substituting 2-chloropyrimidin-4-amine for 5-fluoro-2-nitroaniline toafford compound I-5, obtained as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.17 (d, J=6.7 Hz, 3H), 3.44 (br s, 2H), 3.58-3.59 (m, 1H),7.07 (d, J=5 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.85 (d, J=9 Hz, 1H),8.03-8.08 (m, 2H), 8.33 (br s, 1H), 8.45 (d, J=6 Hz, 1H), 9.15 (d, J=9.2Hz, 1H), 10.99 (s, 1H). MS: m/z

Example 14

Synthesis of(R)-3-((2-fluoropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-8)

The title compound was synthesized in the same manner as I-1substituting 2-fluoropyrimidin-4-amine for 5-fluoro-2-nitroaniline.Heating was done conventionally at 90° C. for 16 h (rather than bymicrowave irradiation) to afford compound I-8 (8 mg, 11% yield),obtained as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ: 1.17 (d,J=6.7 Hz, 3-H), 3.44 (s, 2H), 3.58 (s, 1H), 7.05 (br s, 1H), 7.80 (d,J=8.8 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 8.04 (d, J=4.2 Hz, 1H), 8.07 (d,J=8.8 Hz, 1H), 8.21 (brs, 1H), 8.46 (d, J=4.7 Hz, 1H), 9.15 (d, J=9.2Hz, 1H), 10.98 (s, 1H). MS: m/z 395.32 (M+H).

Example 15

Synthesis of (R)-ethyl4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8-[1,4]diazepino[5′,6′,4,5]thieno[3,2-f]quinolin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate(I-12)

In a 15 mL vial, 1,4-dioxane was added to(R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-J]quinolin-8-one(INT-5) (10 mg, 0.028 mmol) and ethyl4-amino-2-(methylthio)pyrimidine-5-carboxylate (INT-8) (8.83 mg, 0.041mmol) followed by NaOt-Bu (7.96 mg, 0.083 mmol), and BrettPhos-G1precatalyst (4.00 mg, 0.552 μmol). The resulting heterogeneous mixturewas purged with argon for 3 minutes and heated at 80° C. overnight.After completion, the reaction was purified by Preparative-HPLC usingacetonitrile/H₂O (0.1% TFA) to afford compound I-12 (6 mg, 0.012 mmol,43.9% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H),9.23 (d, 1H), 8.86 (d, 1H), 8.69 (d, 1H), 8.10 (m, 2H), 7.81 (d, 1H),7.10 (br.s, 1H), 4.38 (q, 2H), 3.60 (m, 1H), 3.45 (m, 2H), 2.66 (s, 3H),1.35 (d, 3H), 1.18 (t, 3H). MS m/z: 494.9 (M+H).

Example 16

Synthesis of(R)-2-chloro-4-(methyl(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(I-34)

To a stirred solution of(R)-2-chloro-N-(4-methoxybenzyl)-4-(methyl(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(INT-44) (60 mg, 0.1 mmol) in dichloromethane (1.0 mL) were addedtrifluoroacetic acid (1.0 mL, 0.1 mmol) and trifluoromethanesulfonicacid (153.12 mg, 1.0 mmol) at 0° C. The resulting reaction mixture wasstirred at 25° C. for 1h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The residue was dilutedwith water, and the solids formed were filtered and washed with waterthen dried under vacuum. The crude product was purified by preparativeTLC by eluting with 5% methanol in dichloromethane to afford compoundI-34 (6.0 mg, 12%) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.17(d, J=6.7 Hz, 3H), 3.42 (m, 2H), 3.57 (m, 1H), 4.14 (s, 3H), 7.09 (t,J=5.5 Hz, 1H), 7.76 (br s, 1H), 7.84 (d, J=9.9 Hz, 1H), 8.05 (d, J=9.2Hz, 1H), 8.15 (d, J=3.8 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.79 (s, 1H),8.85 (br s, 1H), 9.10 (d, J=9.9 Hz, 1H). MS m/z (M+H): 468.4.

Example 17

Synthesis of(R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(I-9)

To a stirred solution of(R)-2-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(INT-43) (20 mg, 0.03 mmol) in dichloromethane (1.0 mL) were addedtrifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.03 mL,0.3 mmol) at 0° C. The resulting reaction mixture was stirred at 25° C.for 1 h. After completion of the reaction, the reaction mixture wasdiluted with water, and the solids formed were filtered, washed withdichloromethane, and dried. The resulting powder was purified bypreparative TLC by eluting with 5% MeOH in dichloromethane to affordcompound I-9 (11 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆):δ 1.18 (d, J=6.7 Hz, 3H), 3.46 (m, 2H), 3.60 (m, 1H), 7.06 (br s, 1H),7.82 (d, J=8.9 Hz, 1H), 8.01 (br s, 1H), 8.07-8.09 (m, 2H), 8.51 (br s,1H), 8.61 (d, J=9.4 Hz, 1H), 8.90 (s, 1H), 9.26 (d, J=9.5 Hz, 1H), 12.11(br s, 1H). MS: m/z 454.3 (M+H).

Example 18

Synthesis of(R)-3-((6-fluoropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-11)

The title compound was synthesized in the same manner as I-1substituting 6-fluoropyrimidin-4-amine for 5-fluoro-2-nitroaniline.Heating was done conventionally at 100° C. for 16 h (rather than bymicrowave irradiation) to afford compound I-11 as a brown solid. ¹H NMR(400 MHz, DMSO-d₆): δ: 1.17 (d, J=6.7 Hz, 3H), 3.44 (s, 2H), 3.59-3.60(m, 1H), 6.99 (t, J=5 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.89 (d, J=9 Hz,1H), 8.03 (s, 1H), 8.06 (d, J=9 Hz, 1H), 8.17 (s, 1H), 8.59 (d, J=2 Hz,1H), 9.10 (d, J=9 Hz, 1H), 10.93 (s, 1H). MS: m/z 395.1 (M+H).

Example 19

Synthesis of(R)-3-((6-chloropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-7)

The title compound was synthesized in the same manner as I-1substituting 6-chloropyrimidin-4-amine for 5-fluoro-2-nitroaniline.Heating was done conventionally at 100° C. for 16 h (rather than bymicrowave irradiation) to afford compound I-7 as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.17 (d, J=6.7 Hz, 3H), 3.47 (br s, 2H), 3.58 (brs, 1H), 7.00 (br s, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H),8.04-8.08 (m, 2H), 8.46 (s, 1H), 8.64 (s, 1), 9.11 (d, J=9.3 Hz, 1H),10.88 (s, 1H). MS m/z (M+H): 411.3.

Example 20

Synthesis of(R)-3-((6-fluoropyrimidin-4-yl)(methyl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-38)

The title compound was synthesized in the same manner as I-1substituting 6-fluoro-N-methylpyrimidin-4-amine for5-fluoro-2-nitroaniline. Heating was done conventionally at 90° C. for16 h (rather than by microwave irradiation) to afford compound I-38 as alight yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7 Hz, 3H),3.44-3.46 (m, 2H), 3.59-3.60 (m, 1H), 3.68 (s, 3H), 6.88 (s, 1H), 7.10(t, J=5.4 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 8.05(d, J=4.3 Hz, 1H), 8.11 (d, J=8.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 9.18(d, J=9.1 Hz, 1H). MS: m/z 409.3 (M+H).

Example 21

Synthesis of(R)-6-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinamide(I-15)

To a stirred solution of(R)-6-chloro-N-(4-methoxybenzyl)-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)nicotinamide(INT-S1) (20 mg, 0.04 mmol) in dichloromethane:trifluoroacetic acid (2mL, 1:1 ratio), was added trifluoromethanesulfonic acid (52 mg, 0.34mmol) at 0° C. and stirred at room temperature for 2 h. Aftercompletion, the reaction mixture was concentrated under reduced pressureand saturated aqueous NaHCO₃ solution (3 mL) was added at 0° C. andstirred for 20 min. The solid formed was filtered and washed with water,and the crude compound was purified by preparative HPLC to affordcompound I-15 (8 mg, 61 yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-D₆): δ: 1.20 (d, J=6.7 Hz, 3H), 3.44-3.49 (m, 2H), 3.58 (d, J=3.1Hz, 1H), 7.04 (J=5.4 Hz, 1H), 7.29 (d, J=9.2 Hz, 1H), 7.83 (d, J=9 Hz,1H), 7.93 (br s, 1H), 8.08 (d, J=9 Hz, 2H), 8.48 (br s, 1H), 8.72 (s,1H), 9.10 (d, J=9.3 Hz, 1H), 9.27 (s, 1H), 11.97 (s, 1H). MS: m/z 453.28(M+H).

Example 22

Synthesis of (R)-ethyl4-chloro-2-((10-methyl-8-oxo-9,1,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxylate(I-23)

The title compound was synthesized in the same manner as I-1substituting ethyl 2-amino-4-chloro-pyrimidine-5-carboxylate for5-fluoro-2-nitroaniline and(R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(INT-5) for(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12). The title compound I-23 was obtained as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.18 (d, J=6.7 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H),3.45 (br s, 2H), 3.60 (br s, 1H), 4.32 (q, J=7.0 Hz, 2H), 4.29-4.34 (m,2H), 7.07 (t, J=5.0 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 8.03 (d, J=4.0 Hz,1H), 8.06 (d, J=8.8 Hz, 1H), 8.40 (d, J=9.3 Hz, 1H), 8.96 (s, 1H), 9.19(d, J=9.3 Hz, 1H), 11.2 (br s, 1H). MS m/z (M+H): 483.1.

Example 23

Synthesis of(R)-3-((2,6-difluoropyridin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-6)

A solution of(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (50 mg, 0.16 mmol), 2,6-difluoropyridin-4-amine (40.9 mg, 0.3mmol) and cesium carbonate (154 mg, 0.5 mmol) in 1,4-dioxane (5 mL) wasdegassed with argon for 10 min. BINAP (9.8 mg, 0.02 mmol) and Pd₂(dba)₃(14.4 mg, 0.02 mmol) were added, the solution was again degassed withargon for 5 min and then heated to 100° C. for 16 h. After completion ofreaction, the reaction mixture was concentrated under reduced pressure.The resulting crude compound was purified by column chromatography(100-200 silica mesh, 10% methanol in dichloromethane as eluent)followed by concentration of the relevant fractions and furtherpurification by reverse phase HPLC to afford compound I-6 (7 mg, 10%yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): d: 1.17 (d, J=6.7 Hz,3H), 3.43 (s, 2H), 3.59 (d, J=4 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 7.24(d, J=9 Hz, 1H), 7.59 (s, 2H), 7.87 (d, J=9 Hz, 1H), 8.03-8.06 (m, 2H),9.09 (d, J=9 Hz, 1H), 10.51 (s, 1H). MS: m/z 412.1 (M+H).

Example 24

Synthesis of(R)-3-((2-fluoropyridin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-3)

In a 10 mL microwave vial, Pd₂(dba)₃ (21.61 mg, 0.024 mmol), cesiumcarbonate (77 mg, 0.236 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (DavePhos, 18.58mg, 0.047 mmol), 4-amino-2-fluoropyridine (8.82 mg, 0.079 mmol), and(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (25 mg, 0.079 mmol) were dissolved in 0.5 mL of dry t-BuOH. Thereaction was placed under vacuum then backfilled with nitrogen. Thereaction was heated to 100° C. overnight then cooled, filtered andconcentrated to dryness. The residue was redissolved in DMSO andpurified by reverse phase HPLC with 95%-5% H₂O (containing 0.5% TFAv/v)/acetonitrile to afford compound I-3 (0.004 g, 7.8 mol, 10.0%yield). MS: m/z 393.6 (M+H), 391.7 (M−H). ¹H NMR (400 MHz, DMSO-d₆): δ1.13 (d, 3H), 3.39 (m, 2H), 3.55 (m, 1H), 6.94 (br s, 1H), 7.20 (d, 1H),7.81 (d, 1H), 7.99 (m, 4H), 9.02 (d, 1H), 10.21 (s, 1H).

Example 25

Synthesis of(R)-3-((2-chloropyridin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(1-4)

The title compound was synthesized in the same manner as I-3substituting 4-amino-2-chloro pyridine for 4-amino-2-fluoropyridine toafford compound I-4 (0.003 g, 5.7 μmol, 7.3% yield). MS: m/z 409.7(M+H), 407.8 (M−H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.13 (d, 3H), 3.38 (brs, 2H), 3.55 (m, 1H), 6.95 (br s, 1H), 7.17 (d, 1H), 7.72 (d, 1H), 7.78(d, 1H), 8.01 (m, 2H), 8.16 (d, 1H), 9.03 (d, 1H).

Example 26

Synthesis of(R)-3-((2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-32)

In a 5 mL microwave vial,(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (0.04 g, 0.126 mmol), BINAP (7.84 mg, 0.013 mmol), Pd(OAc)₂(8.48 mg, 0.013 mmol), cesium carbonate (0.082 g, 0.252 mmol) and2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a) (0.028 g,0.138 mmol) were suspended in 3 mL of 1,4-dioxane. The reaction wasplaced under vacuum, sonicated, then backfilled with nitrogen. Thereaction was irradiated in a Biotage Explorer microwave at 130° C. for 1h. The reaction was cooled, filtered and concentrated to dryness. Theresidue was redissolved in DMSO and purified by reverse phase HPLC with95%-5% H₂O (containing 0.5% TFA v/v)/acetonitrile to afford compoundI-32 (0.017 g, 0.035 mmol, 28.0% yield). MS: m/z 466.1 (M+H), 463.8(M−H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, 3H), 2.88 (s, 6H), 3.43 (m,2H), 3.59 (m, 3H), 4.67 (m, 2H), 7.04 (m, 1H), 7.78 (br s, 1H), 7.88 (d,1H), 8.08 (d, 1H), 9.14 (d, 1H), 9.89 (br s, 1H), 10.93 (s, 1H).

Example 27

Synthesis of(R)-3-((6-fluoro-2-(oxetan-3-yloxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-37)

The title compound was synthesized in the same manner as I-32substituting 6-fluoro-2-(oxetan-3-yloxy)pyrimidin-4-amine (INT-9a) for2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine to afford compoundI-37 (0.0033 g, 7.07 μmol, 5.6% yield). MS: m/z 467.1 (M+H), 464.6(M−H).

Example 28

Synthesis of(R)-3-((6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-39)

The title compound was synthesized in the same manner as I-32substituting 6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine(INT-15a) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine(S3-3a) to afford compound I-39 (0.01 g, 0.02 mmol, 12.9% yield). MS:m/z 495.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, 3H), 1.38 (s,3H), 3.55 (m, 3H), 4.33 (d, 2H), 4.42 (s, 2H), 4.51 (d, 2H), 7.03 (t,1H), 7.75 (br s, 1H), 7.88 (d, 1H), 8.07 (m, 2H), 9.12 (d, 1H), 10.91(s, 1H).

Example 29

Synthesis of(R)-3-((4-fluoro-6-(oxetan-3-yloxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-42)

The title compound was synthesized in the same manner as I-32substituting 4-fluoro-6-(oxetan-3-yloxy)pyrimidin-2-amine (INT-9b) for2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine (S3-3a). Thisyielded compound I-42 (0.02 g, 0.04 mmol, 26.7% yield). MS: m/z 467.1(M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.20 (d, 3H), 3.47 (m, 2H), 3.62 (m,1H), 4.64 (m, 2H), 4.97 (m, 2H), 5.67 (m, 1H), 6.28 (sm 1H), 7.08 (br s,1H), 7.77 (d, 1H), 8.07 (d, 1H), 8.29 (d, 1H), 9.18 (d, 1H), 10.66 (s,1H).

Example 30

Synthesis of(R)-3-((4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-43)

The title compound was synthesized in the same manner as I-32substituting 4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine(INT-15b) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine.This yielded compound I-43 (0.01 g, 0.02 mmol, 13.8% yield). MS: m/z495.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, 3H), 1.38 (s, 3H),3.46 (br s, 2H), 3.61 (m, 1H), 4.33 (d, 2H), 4.52 (m, 4H), 6.25 (s, 1H),7.17 (s, 1H), 7.77 (d, 1H), 8.07 (d, 1H), 8.40 (d, 1H), 9.17 (d, 1H),10.64 (s, 1H).

Example 31

Synthesis of(R)-3-((6-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-40)

The title compound was synthesized in the same manner as I-32substituting (S)-6-fluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-amine(INT-23) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine toafford compound I-40 as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s,1H), 9.11 (d, 1H), 8.06 (d, 2H), 7.84 (d, 2H), 7.53 (br s, 1H), 7.01 (s,1H), 5.47 (t, 1H), 3.95-3.78 (m, 4H), 3.78-3.30 (m, 4H), 2.27-2.01 (m,2H), 1.17 (d, 3H). MS m/z: 480.8 (M+H).

Example 32

Synthesis of(R)-3-((4-fluoro-6-(((S)-tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-50)

The title compound was synthesized in the same manner as I-32substituting (S)-4-fluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine(INT-22) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine toafford compound I-50 as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.61 (s,1H), 9.15 (d, 1H), 8.36 (d, 1H), 8.05 (d, 2H), 7.76 (d, 1H), 7.05 (s,1H), 6.19 (s, 1H), 4.01-3.83 (m, 4H), 3.60-3.45 (m, 3H), 2.48-2.01 (m,2H), 1.18 (d, 3H). MS m/z: 480.8 (M+H).

Example 33

Synthesis of(R)-3-((6-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-41)

The title compound was synthesized in the same manner as I-32substituting (R)-6-fluoro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-amine(INT-27) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine toafford compound I-41 as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.83 (s,1H), 9.11 (d, 1H), 8.05 (d, 2H), 7.84 (d, 2H), 7.65 (br s, 1H), 7.01 (s,1H), 5.48 (t, 1H), 3.95-3.82 (m, 4H), 3.51 (m, 1H), 3.43 (m, 2H),2.30-2.06 (m, 2H), 1.17 (d, 3H). MS m/z: 481.0 (M+H).

Example 34

Synthesis of(R)-3-((6-fluoro-2-(2-methoxyethoxy)pyrmidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-44)

The title compound was synthesized in the same manner as I-32substituting 6-fluoro-2-(2-methoxyethoxy)pyrimidin-4-amine (INT-19) for2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine to afford compoundI-44 (18 mg, 0.038 mmol, 27.2% yield) as solid. ¹H NMR (400 MHz,DMSO-d6): δ 10.82 (s, 1H), 9.10 (d, 1H), 8.05 (m, 2H), 7.84 (m, 2H),7.01 (br s, 1H), 4.42 (t, 2H), 3.67 (m, 2H), 3.58 (m, 1H), 3.42 (m, 2H),3.30 (s, 3H), 1.16 (d, 3H). MS m/z: 469.0 (M+H).

Example 35

Synthesis of(R)-3-((4-fluoro-6-(((R)-tetrahydrofuran-3-yl)oxy)pyrimidin-32-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-46)

The title compound was synthesized in the same manner as I-32substituting (R)-4-fluoro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine(INT-26) for 2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine toafford compound I-46 as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.61 (s,1H), 9.14 (d, 1H), 8.35 (d, 1H), 8.04 (d, 2H), 7.75 (d, 1H), 7.04 (s,1H), 6.18 (s, 1H), 5.57 (t, 1H), 3.98 (m, 1), 3.87-3.77 (m, 3H), 3.61(m, 1H), 3.44 (m, 2H), 2.31 (m, 1H), 2.04 (m, 1H), 1.17 (d, 3H). MS m/z:481.0 (M+H).

Example 36

Synthesis of(R)-3-((4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-45)

The title compound was synthesized in the same manner as I-32substituting 4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-amine (INT-18) for2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine to afford compoundI-45 as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.15 (d,1H), 8.37 (d, 1H), 8.07 (m, 2H), 7.76 (d, 1H), 7.05 (br s, 1H), 6.20 (s,1H), 4.52 (t, 2H), 3.69 (t, 2H), 3.59 (m, 1H), 3.44 (m, 2H), 3.30 (s,3H), 1.17 (d, 3H). MS m/z: 469.0 (M+H).

Example 37

Synthesis of(R)-3-((6-chloro-2-(methoxymethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-51)

The title compound was synthesized in the same manner as I-32substituting 6-chloro-2-(methoxymethyl)pyrimidin-4-amine for2-(2-(dimethylamino)ethoxy)-6-fluoropyrimidin-4-amine. This yieldedcompound I-51 (0.025 g, 0.06 mmol, 10.7% yield). MS: m/z 454.9 (M+H). ¹HNMR (400 MHz, DMSO-d₆): δ 1.18 (d, 3H), 3.41 (s, 3H), 3.44 (m, 3H), 4.49(s, 2H), 7.05 (br s, 1H), 7.85 (d, 1H), 8.08 (m, 2H), 9.12 (d, 1H),10.99, (s, 1H).

Example 38

Synthesis of(10R)-3-((6-fluoro-2-((I-methylpiperidin-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(1:1 Mixture of Diastereomers) (I-47)

A solution of(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (150 mg, 0.47 mmol) and(rac)-6-fluoro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine (INT-10)(128.1 mg, 0.56 mmol) dissolved in 1,4-dioxane (6.0 mL) was brieflydegassed by applying vacuum and then flushed with nitrogen thrice. Tothe above solution were added cesium carbonate (461.3 mg, 1.41 mmol),Pd₂(dba)₃ (43.2 mg, 0.05 mmol) and Xantphos (27.3 mg, 0.05 mmol) at roomtemperature and the solution was degassed again for 5 minutes. Theresulting reaction mixture was stirred at 100° C. for 6 h. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure, whereupon solids formed. The solids obtained werewashed with water, diethyl ether and acetone to afford compound I-47 (30mg, 12%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d,J=6.6 Hz, 3H), 1.43-1.57 (m, 2H), 1.73 (m, 1H), 1.97-2.15 (m, 2H), 2.19(s, 4H), 2.5 (m, 1H), 2.88 (d, J=9.4 Hz, 1H), 3.44-3.49 (m, 2H),3.55-3.59 (m, 1H), 4.99 (m, 1H), 6.99 (s, 1H), 7.69 (s, br, 1H), 7.79(d, J=7.2 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 8.01-8.06 (m, 2H), 9.10 (d,J=9.1 Hz, 1H), 10.76 (s, br, 1H). MS m/z (M+H): 508.3.

Example 39

Synthesis of(R)-3-((6-fluoro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-48)

The title compound was synthesized in the same manner as I-47substituting6-fluoro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine (INT-11)for (rac)-6-fluoro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine(INT-10) to afford compound I-48 as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.18 (d, J=6.4 Hz, 3H), 2.12 (s, 3H), 2.29 (br s, 4H),2.49 (br s, 4H), 2.68 (br s, 2H), 3.43 (br s, 2H), 3.58 (br s, 1H), 4.41(s, 2H), 6.99 (s, 1H), 7.58 (br s, 1H), 7.78-7.85 (m, 2H), 8.00-8.05 (m,2H), 9.12 (d, J=9.1 Hz, 1H), 10.39 (br s, 1H). MS m/z (M+H): 537.2.

Example 40

Synthesis of(R)-3-((6-fluoro-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-49)

The title compound was synthesized in the same manner as I-47substituting(R)-6-fluoro-2-((I-methylpyrrolidin-3-yl)oxy)pyrimidin-4-amine (INT-12)for (rac)-6-fluoro-2-[(1-methyl-3-piperidyl)oxy]pyrimidin-4-amine(INT-10) to compound I-49 (8.0 mg, 16%) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 1.19 (d, J=6.7 Hz, 3H), 2.27 (s. 3H), 2.31-2.40(m, 2H), 2.61-2.68 (m, 3H), 2.82-2.84 (m, 1H), 3.44 (br s, 2H), 3.59 (brs, 1H), 5.33 (br s, 1H), 6.99 (br s, 1H), 7.49 (br s, 1H), 7.83-7.85 (m,2H), 8.01 (br s, 1H), 8.05 (d, J=8.8 Hz, 1H), 9.13 (d, J=9.3 Hz, 1H),10.75 (br s, 1H). MS m/z (M+H): 494.5.

Example 41

Synthesis of(10R)-3-((6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(1:1 Mixture of Diastereomers) (I-59)

A solution of(R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-5) (100 mg, 0.3 mmol) and(rac)-6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine (S4-4)(67 mg, 0.3 mmol) dissolved in 1,4-dioxane (5.0 mL) was briefly degassedby applying vacuum and then flushed with nitrogen thrice. To the abovesolution were added cesium carbonate (269.8 mg, 0.8 mmol), Pd₂(dba)₃(25.3 mg, 0.03 mmol) and xantphos (15.9 mg, 0.03 mmol) at roomtemperature. The resulting mixture was further degassed and stirred at100° C. for 6 h. After completion, the reaction mixture wasconcentrated, and a solid formed. The solid obtained was washed withwater, dichloromethane and purified by preparative-HPLC to affordcompound I-59 (13 mg, 9%) as a red solid. ¹H NMR (400 MHz, CD₃OD): δ1.35 (d, J=6.8 Hz, 3H), 1.88-1.97 (m, 2H), 2.19-2.30 (m, 2H), 2.94 (s,3H), 3.07-3.15 (m, 2H), 3.51-3.60 (m, 3H), 3.70-3.79 (m, 1H), 3.88-3.91(m, 1H), 5.57 (br s, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.86 (d, J=8.8 Hz,1H), 8.00 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 9.08 (d, J=9.2 Hz, 1H). MSm/z (M+H): 524.6.

Example 42

Synthesis of(R)-3-((6-chloro-2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-60)

The title compound was synthesized in the same manner as I-59substituting(R)-6-chloro-2-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-4-amine (INT-28)for (rac)-6-chloro-2-(1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine toafford compound I-60 (10.0 mg, 7%) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.19 (d, J=6.5 Hz, 3H), 2.27 (s, 3H), 2.32-2.36 (m,2H), 2.66-2.68 (m, 3H), 2.83-2.87 (m, 1H), 3.45 (br s, 2H), 3.60 (br s,1H), 5.34 (br s, 1H), 6.98 (br s, 1H), 7.72-7.74 (m, 1H), 7.81 (d, J=8.8Hz, 1H), 7.91-7.97 (m, 2H), 8.06 (d, J=8.9 Hz, 1H), 9.14 (d, J=9.3 Hz,1H), 10.7 (br s, 1H). MS m/z (M+H): 510.4.

Example 43

Synthesis of(R)-3-((6-chloro-2-(2-methoxyethoxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-67)

The title compound was synthesized in the same manner as I-59substituting 2-chloro-6-(2-methoxyethoxy)pyrimidin-4-amine (S5-4) for(rac)-6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine to givecompound I-67 (25 mg, 18%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.19 (d, J=6.6 Hz, 3H), 3.34 (s, 3H), 3.45 (br s, 2H), 3.60 (br s,1H), 3.68 (t, J=4.4 Hz, 2H), 4.44 (t, J=4.4 Hz, 2H), 6.98 (br s, 1H),7.79-7.82 (m, 2H), 7.97-7.98 (m, 2H), 8.06 (d, J=8.8 Hz, 1H), 9.14 (d,J=9.3 Hz, 1H), 10.73 (br s, 1H). MS m/z (M+H): 485.4.

Example 44

Synthesis of(R)₃-((6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-66)

The title compound was synthesized in the same manner as I-59substituting6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine (INT-29)for 6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine togive compound I-66 (10 mg, 4.1%) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.19 (d, J=6.7 Hz, 3H), 1.88 (s, 1H), 2.13 (s, 3H),2.30 (br s, 4H), 2.50 (br s, 4H), 2.67-2.70 (t, J=5.7 Hz, 2H), 3.45 (brs, 2H), 3.60 (br s, 1H), 4.41-4.43 (t, J=5.6 Hz, 2H), 7.80-7.91 (br m,3H), 7.98 (d, J=3.7 Hz, 1H), 8.06 (d, J=8.9 Hz, 1H), 9.13 (d, J=9.3 Hz,1H), 10.72 (br s, 1H). MS m/z (M+H): 553.1.

Example 45

Synthesis of(R)-3-((4-chloro-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-61)

The title compound was synthesized in the same manner as I-59substituting6-chloro-2-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-4-amine (INT-46)for (rac)-6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine toafford compound I-61 (14 mg, 14.6%) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.19 (d, J=6.6 Hz, 3H), 2.11 (s, 3H), 2.27 (br s, 4H),2.49 (br s, 4H), 2.67-2.70 (t, J=5.6 Hz, 2H), 3.45 (br s, 2H), 3.60 (brs, 1H), 4.49-4.52 (t, J=5.6 Hz, 2H), 6.54 (s, 1H), 7.01 (br s, 1H), 7.76(d, J=8.8 Hz, 1H), 7.97 (d, J=3.2 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 8.39(d, J=9.2 Hz, 1H), 9.15 (d, J=9.3 Hz, 1H), 10.39 (br s, 1H). MS m/z(M+H): 553.2.

Example 46

Synthesis of(R)-3-((4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-69)

The title compound was synthesized in the same manner as I-59substituting 4-chloro-6-(2-methoxyethoxy)pyrimidin-2-amine (INT-45) for(rac)-6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine to givecompound I-69 (8.0 mg, 12%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.19 (d, J=6.7 Hz, 3H), 3.30 (s, 3H), 3.45 (s, 2H),3.59-3.60 (br m, 1H), 3.70 (t, J=4.5 Hz, 2H), 4.52 (t, J=4.3 Hz, 2H),6.57 (s, 1H), 7.00 (br s, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.96 (br s, 1H),8.03 (d, J=8.9 Hz, 1H), 8.40 (d, J=9.3 Hz, 1H), 9.15 (d, J=9.4 Hz, 1H),10.41 (br s, 1H). MS m/z (M+H): 485.1.

Example 47

Synthesis of (R)-methyl4-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-2-carboxylate(I-70)

The title compound was synthesized in the same manner as I-59substituting methyl 4-amino-6-chloropyrimidine-2-carboxylate (S6-5) for(rac)-6-chloro-2-((l-methylpiperidin-3-yl)oxy)pyrimidin-4-amine to givecompound I-70 (10.0 mg, 11%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.19 (d, J=6.7 Hz, 3H), 3.45 (br s, 2H), 3.60 (br s, 1H),3.92 (s, 3H), 6.98 (br s, 1H), 7.80 (br s, 1H), 7.87 (d, J=8.9 Hz, 1H),7.98 (br s, 1H), 8.08 (d, J=8.9 Hz, 1H), 8.67 (br s, 1H), 9.14 (d, J=9.2Hz, 1H), 11.23 (br s, 1H). MS m/z (M+H): 469.0.

Example 48

Synthesis of(R)-3-((6-fluoro-2-(piperidin-1-ylmethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-74)

The title compound was synthesized in the same manner as I-59substituting 6-fluoro-2-(piperidin-1-ylmethyl)pyrimidin-4-amine (S7-8)for (rac)-6-chloro-2-((l-methylpiperidin-3-yl)oxy)pyrimidin-4-amine togive compound I-74 (44 mg, 29%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.18 (d, J=6.8 Hz, 3H), 1.38 (m, 2H), 1.51 (m, 4H),2.45-2.48 (m, 4H), 3.44 (m, 2H), 3.52 (s, 2H), 3.59 (m, 1H), 6.96 (m,1H), 7.71 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.96 (m, 1H),8.03-8.05 (m, 2H), 9.08 (d, J=9.2 Hz, 1H), 10.89 (br s, 1H). MS m/z(M+H): 492.4.

Example 49

Synthesis of(R)-3-((6-fluoro-2-((4-methylpiperazin-1-yl)methyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-73)

The title compound was synthesized in the same manner as I-59substituting6-fluoro-2-((4-methylpiperazin-1-yl)methyl)pyrimidin-4-amine (INT-30)for (rac)-6-chloro-2-((1-methylpiperidin-3-yl)oxy)pyrimidin-4-amine togive compound I-73 (40 mg, 39%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.18 (d, J=6.8 Hz, 3H), 2.14 (s, 3H), 2.32-2.40 (m, 4H),2.52-2.58 (m, 4H), 3.44 (m, 2H), 3.55 (s, 2H), 3.59-3.65 (m, 1H), 6.96(m, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.97 (m, 1H),8.03-8.05 (m, 2H), 9.09 (d, J=9.6 Hz, 1H), 10.89 (br s, 1H). MS m/z(M+H): 507.5.

Example 50

Synthesis of(R)-3-((4-chloro-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-10)

In a 10 mL round-bottomed flask was(R)-3-bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-31) (0.03 g, 0.083 mmol),4-chloro-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (0.019 g,0.083 mmol, see section “synthesis of intermediates” for synthesis), andK₂CO₃(0.034 g, 0.248 mmol) in 1,4-Dioxane (5 mL) to give a yellowsuspension. Pd₂(dba)₃ (7.58 mg, 8.28 μmol) and2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine(DavePhos 6.52 mg, 0.017 mmol) were added and the reaction was heated toreflux under nitrogen for 4 hours. The reaction was then cooled,filtered over a short silica plug, and concentrated. The resultingresidue was redissolved in 1 mL of DMSO and purified by reverse phaseHPLC with 95%-5% H₂O (containing 0.5% TFA v/v)/acetonitrile to yieldcompound I-10 (0.0027 g, 5.29 μmol, 6.39% yield). MS: m/z 510.1 (M+H),507.7 (M−H).

Example 51

Synthesis of(R)-3-((4-chloropyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-13)

The title compound was synthesized in the same manner as I-10substituting 4-chloropyrimidine-2-amine for4-chloro-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine to affordcompound I-13 (0.0018 g, 4.38 μmol, 5.29% yield). MS: m/z 410.2 (M+H).

Example 52

Synthesis of(R)-3-((2-(dimethylamino)ethyl)(6-fluoropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-33)

In a 10 mL microwave vial Pd₂(dba)₃ (7.20 mg, 7.87 μmol), cesiumcarbonate (0.051 g, 0.157 mmol),dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos,7.34 mg, 0.016 mmol),N-(6-fluoropyrimidin-4-yl)-N²,N²-dimethylethane-1,2-diamine (INT-32)(0.017 g, 0.094 mmol), and(R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S1-12) (0.025 g, 0.079 mmol) were dissolved in 5 mL of dry 1,4-dioxane.The reaction was placed under vacuum, sonicated, and backfilled withnitrogen. The reaction was irradiated in a Biotage Explorer microwave at130° C. for 3 hours. The reaction was cooled, filtered and concentratedto dryness. The residue was redissolved in DMSO and purified by reversephase HPLC with 95%-5% H₂O (containing 0.5% TFA v/v)/acetonitrile toafford compound I-33 (0.0066 g, 0.014 mmol, 18.02% yield). ¹H NMR (400MHz, DMSO-d₆): δ 1.18 (d, 3H), 2.99 (s, 6H), 3.48 (m, 6H), 3.60 (m, 2H),4.61 (m, 2H), 7.17 (t, 1H), 7.85 (d, 1H), 7.96 (d, 1H), 7.18 (m, 2H),8.61 (s, 1H), 9.24 (d, 1H), 9.58 (br s, 1H).

Example 53

Synthesis of(R)-3-((6-fluoropyrimidin-4-yl)(2-methoxyethyl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-36)

The title compound was synthesized in the same manner as I-33substituting 6-fluoro-N-(2-methoxyethyl)pyrimidin-4-amine (INT-33) forN1-(6-fluoropyrimidin-4-yl)-N2,N2-dimethylethane-1,2-diamine to affordcompound I-36 (0.0019 g, 4.20 μmol, 3.34% yield). MS: m/z 453.0 (M+H),450.8 (M−H).

Example 54

Synthesis of(R)-3-((2-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-52)

In a 20 mL vial,(R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-6) (0.072 g, 0.241 mmol) was suspended in 3 mL of dry DMF. Sodiumhydride (60% by wt. in dispersion oil, 9.62 mg, 0.241 mmol) was addedand the reaction was warmed to 90° C. The starting material slowly goesinto solution as gas is released and color becomes dark amber. After 10min of heating, the reaction is cooled to 0° C. and2,4-difluoropyrimidine (0.028 g, 0.241 mmol) was added dropwise. Thereaction was stirred at room temperature or warmed to 50° C. Uponcompletion, the reaction was quenched with saturated NH₄Cl (aq.) andpoured into water. The reaction was extracted three times withdichloromethane, and the organic extracts were combined, dried oversodium sulfate and concentrated under vacuum. The resulting residue wasredissolved in DMSO and purified by reverse phase HPLC with 95%-5% H₂O(containing 0.5% TFA v/v)/acetonitrile to afford compound I-52 (0.036 g,0.091 mmol, 37.9% yield). MS: m/z 395.9 (M+H), 393.7 (M−H). ¹H NMR (400MHz, DMSO-d₆): δ 1.17 (d, 3H), 3.43 (m, 2H), 3.59 (m, 1H), 5.72 (s, 1H),7.14 (t, 1H) 7.39 (m, 1H), 7.64 (d, 1H), 7.84 (d, 1H), 8.15 (m, 2H),8.77 (m, 1H), 9.36 (d, 1H).

Example 55

Synthesis of(R)-3-((6-chloro-2-methylpyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-58)

The title compound was synthesized in the same manner as I-52substituting 4,6-dichloro-2-methylpyrimidine for 2,4-difluoropyrimidineto afford compound I-58 (0.005 g, 0.01 mmol, 16.9% yield). MS: m/z 425.9(M+H), 423.6 (M−H). ¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (d, 3H), 3.59 (m,1H), 3.75 (d, 1H), 3.84 (m, 1H), 5.36 (br s, 1H), 7.07 (br s, 1H), 7.13(s, 1H), 7.26 (s, 1H), 7.36 (d, 1H), 7.92 (d, 2H), 7.99 (d, 1H) 9.00 (d,1H).

Example 56

Synthesis of(R)-3-((6-chloro-2-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-57)

The title compound was synthesized in the same manner as I-52substituting 4,6-dichloro-2-(methoxymethyl)pyrimidine for2,4-difluoropyrimidine to afford compound I-57 (0.025 g, 0.055 mmol, 11%yield) MS: m/z 455.8 (M+H), 453.6 (M−H). ¹H NMR (400 MHz, DMSO-d₆): δ1.18 (d, 3H), 3.27 (s, 3H), 3.61 (m, 3H), 4.42 (s, 2H), 7.15 (br s, 1H),7.55 (s, 1H), 7.60 (d, 1H), 7.83 (d, 1H), 8.16 (m, 2H), 9.35 (d, 1H).

Example 57

Synthesis of(R)-3-((6-chloropyrazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-55)

The title compound was synthesized in the same manner as I-52substituting 2,6-dichloropyrazine for 2,4-difluoropyrimidine to affordcompound I-55 (2.4 mg, 4.51 μmol, 9.01% yield) as a yellow solid. LCMSm/z: 411.8 [M+H].

Example 58

Synthesis of(R)-3-((6-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-56)

The title compound was synthesized in the same manner as I-52substituting 4,6-dichloropyrimidine for 2,4-difluoropyrimidine to affordcompound I-56. MS m/z: 411.8 [M+H]. ¹H-NMR (400 MHz, CDCl₃): δ 9.02 (d,1H), 8.65 (s, 1H), 8.04-7.92 (m, 2H), 7.39 (d, 1H), 7.30 (s, 1H), 3.86(m, 1H), 3.80-3.72 (m, 1H), 3.60 (m, 1H), 1.44 (d, 3H).

Example 59

Synthesis of(R)-3-((2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-53)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloropyrimidine for 2,4-difluoropyrimidine to affordcompound I-53 (30 mg, 20%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.20 (d, J=6.6 Hz, 3H), 3.46 (br s, 2H), 3.60 (br s, 1H), 7.10 (br s,1H), 7.42 (d, J=5.6 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.9 Hz,1H), 8.04 (br s, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.74 (d, J=5.6 Hz, 1H),9.37 (d, J=9.0 Hz, 1H). MS m/z (M+H): 412.3.

Example 60

Synthesis of(R)-3-((6-fluoro-2-methylpyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-65)

The title compound was synthesized in the same manner as I-52substituting 4,6-difluoro-2-methylpyrimidine for 2,4-difluoropyrimidineto afford compound I-65 as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.33(d, 1H), 8.15 (m, 2H), 7.82 (m, 1H), 7.56 (d, 1H), 7.13 (br s, 1H), 7.03(s, 1H), 3.58-3.43 (m, 3H), 2.40 (s, 3H), 1.17 (d, 3H). MS m/z: 409.9(M+H).

Example 61

Synthesis of (R)-methyl4-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidine-2-carboxylate(I-71)

The title compound was synthesized in the same manner as I-52substituting methyl 4,6-dichloropyrimidine-2-carboxylate for2,4-difluoropyrimidine to afford compound I-71 (16 mg, 11.3%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.20 (d, J=6.6 Hz, 3H), 3.46(br s, 2H), 3.61 (br s, 1H), 3.82 (s, 3H), 7.10 (br s, 1H), 7.61 (d,J=9.1 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 8.05 (br s, 1H),8.17 (d, J=8.9 Hz, 1H), 9.37 (d, J=9.1 Hz, 1H). MS m/z

Example 62

Synthesis of(R)-3-((6-chloro-2-(hydroxymethyl)pyrmidin-4-yl)oxy)-10-methyl-9,10,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-68)

To a solution of (R)-methyl4-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidine-2-carboxylate(I-71) (30 mg, 0.06 mmol) in tetrahydrofuran (3.0 mL),diisobutylaluminium hydride (1M) (72.6 mg, 0.50 mL, 0.5 mmol) was addedat 0° C. The resulting reaction mixture was stirred at room temperaturefor 2 h. After completion, the reaction mixture was quenched withsaturated ammonium chloride solution (5 mL) and extracted with ethylacetate (2×15 mL). The organic layer was washed with (2×10 mL) waterfollowed by brine (1×10 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by preparative TLC to afford compound I-68 (6.0 mg,18%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (d, J=6.6 Hz,3H), 3.46 (br s, 2H), 3.60 (br s, 1H), 4.43 (d, J=6.6 Hz, 2H), 5.34 (t,J=6.2 Hz, 1H), 7.09 (br s, 1H), 7.44 (s, 1H), 7.57 (d, J=9.0 Hz, 1H),7.82 (d, J=8.9 Hz, 1H), 8.04 (br s, 1H), 8.15 (d, J=8.8 Hz, 1H), 9.35(d, J=9.1 Hz, 1H). MS m/z (M+H): 442.4.

Example 63

Synthesis of(R)-3-((4-chloro-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-62)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloro-6-(pyrrolidin-1-yl)-1,3,5-triazine (INT-34)for 2,4-difluoropyrimidine to afford compound I-62. MS: m/z: 481.9[M+1]. ¹H-NMR (400 MHz, CDCl₃): δ 8.98 (d, 1H), 7.99-7.88 (m, 2H), 7.32(d, 1H), 6.12 (s, 1H), 5.28 (t, 1H), 3.87-3.79 (m, 1H), 3.76-3.69 (m,1H), 3.63 (t, 2H), 3.60-3.52 (m, 1H), 3.44 (t, 2H), 2.02-1.89 (m, 4H),1.40 (d, 3H).

Example 64

Synthesis of(R)-3-((4-chloro-6-morpholino-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-63)

The title compound was synthesized in the same manner as I-52substituting 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (INT-35) for2,4-difluoropyrimidine to afford compound I-63. MS: m/z 497.9 [M+H].¹H-NMR (400 MHz, DMSO-d6): δ 9.33 (d, 1H), 8.20-8.13 (m, 2H), 7.87 (d,1H), 7.62 (d, 1H), 7.15 (s, 1H), 3.80-3.70 (m, 3H), 3.68-3.62 (t, 2H),3.59-3.53 (m, 4H), 3.45 (m, 2H), 1.19 9d, 3H).

Example 65

Synthesis of(R)-3-((4-chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-64)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloro-6-(piperidin-1-yl)-1,3,5-triazine (INT-36) for2,4-difluoropyrimidine to afford compound I-64. MS: m/z: 495.8 [M+H].

Example 66

Synthesis of(R)-3-((4-chloro-6-(dimethylamino)-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-75)

The title compound was synthesized in the same manner as I-52substituting 4,6-dichloro-N,N-dimethyl-1,3,5-triazin-2-amine (INT-37)for 2,4-difluoropyrimidine to afford compound I-75. MS: m/z 455.8 [M+H].¹H-NMR (400 MHz, DMSO-d6): δ 9.33 (d, 1H), 8.21-8.14 (m, 2H), 7.88 9d,1H), 7.63 (d, 1H), 7.15 (s, 1H), 3.65-3.57 (m, 1H), 3.50-3.44 (m, 2H),3.12 (s, 3H0, 2.96 (s, 3H), 1.19 9d, 3H).

Example 67

Synthesis of(R)-3-((4-chloro-6-methoxy-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-76)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloro-6-methoxy-1,3,5-triazine (INT-38) for2,4-difluoropyrimidine to afford compound I-76. MS: m/z 442.7 [M+H].¹H-NMR (400 MHz, DMSO-d6): δ 9.38 (d, 1H), 8.24-8.14 (m, 2H), 7.92-7.87(m, 1H), 7.71-7.66 (m, 1H), 7.17 (s, 1H), 3.96 (s, 3H), 3.66-3.56 (m,1H), 3.50-3.40 (m, 2H), 1.19 (d, 3H).

Example 68

Synthesis of(R)-3-((4-chloro-6-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-77)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloro-6-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazine(INT-39) for 2,4-difluoropyrimidine to afford compound I-77. MS: m/z517.8 [M+H].

Example 69

Synthesis of(R)-3-((4-chloro-6-(3,3-difluoropiperidin-1-yl)-1,3,5-triazin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-78)

The title compound was synthesized in the same manner as I-52substituting 2,4-dichloro-6-(3,3-difluoropiperidin-1-yl)-1,3,5-triazine(INT-40) for 2,4-difluoropyrimidine to afford compound I-78. MS: m/z531.8 [M+H]. ¹H-NMR (400 MHz, DMSO-d6): δ 9.34 (dd, 1H), 8.20 (dd, 1H),8.16 (d, 1H), 7.88 (dd, 1H), 7.66 (dd, 1H), 7.16 (s, 1H), 4.15 (t, 1H),3.97 (t, 2H), 3.84 (t, 3H), 3.65 (m, 2H), 2.12 (m, 2H), 1.78-1.60 (m,2H), 1.19 (d, 3H).

Example 70

Synthesis of(R)-3-((6-chloropyridazin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one

In microwave vial, NaH (26.7 mg, 0.668 mmol) was added to INT-6 (50 mg,0.167 mmol) in DMF (4 mL) and conventionally heated at 55° C. for onehour. Then reaction mixture was cooled to 0° C. and added3,5-dichloropyridazine (49.8 mg, 0.334 mmol) in 0.5 ml of DMF. Resultingmixture was irradiated at 100° C. for 1 h 45 min. After completion ofthe reaction, the crude mixture was purified directly by prep-HPLC usingCH₃CN/H₂O (0.1% Formic acid) as eluents to afford I-79 (15 mg, 0.036mmol, 21.80% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.43 (s,1H), 9.34 (d, 1H), 8.14-8.07 (m, 3H), 7.74 (d, 1H), 7.56 (d, 1H), 7.10(br t, 1H), 3.44-3.30 (m, 3H, merged with DMSO-H₂O peak), 1.16 (d, 3H).MS m/z=411.8 (M+1⁺).

Example 71

Synthesis of(R)-3-((6-fluoropyrimidin-4-yl)thio)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-54)

To a suspension of sodium hydride (22.83 mg, 0.9 mmol) indimethylformamide (1.0 mL),((R)-3-mercapto-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(INT-7) (100 mg, 0.3 mmol) and 4,6-difluoropyrimidine (73.6 mg, 0.6mmol) were added at room temperature. The resulting reaction mixture wasstirred at 90° C. for 2h. After completion of reaction, the reactionmixture was quenched with water and extracted with 5% methanol indichloromethane (3×5 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The crudematerial obtained was purified by preparative TLC to afford compoundI-54 (15 mg, 10%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19(d, J=6.7 Hz, 3H), 3.46 (br s, 2H), 3.61 (br s, 1H), 7.11 (br s, 1H),7.48 (s, 1H), 7.92-7.96 (m, 2H), 8.05 (br s, 1H), 8.20 (d, J=8.9 Hz,1H), 8.78 (br s, 1H), 9.25 (d, J=9.0 Hz, 1H). MS: m/z 412.3 (M+H).

Example 72

Synthesis of(R)-3-((2-chloropyrimidin-4-yl)thio)-10-methy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-72)

The title compound was synthesized in the same manner as I-54substituting 2,4-dichloropyrimidine for 4,6-difluoropyrimidine to affordcompound I-72 (25 mg, 18%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 1.19 (d, J=6.6 Hz, 3H), 3.45 (br m, 2H), 3.60 (br m, 1H), 7.12 (br s,1H), 7.57 (d, J=5.4 Hz, 1H), 77.95-7.97 (m, 2H), 8.07 (br s, 1H), 8.21(d, J=8.9 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 9.26 (d, J=8.9 Hz, 1H). MSm/z (M+H): 428.3.

Example 73

Synthesis of(S)-3-((6-fluoropyrimidin-4-yl)amino)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-17)

To a stirred solution of(S)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1) (50 mg, 0.15 mol) 6-fluoropyrimidin-4-amine (33.9 mg, 0.3 mmol)in 1,4-dioxane (10 mL) was added cesium carbonate (146.42 mg, 0.45mmol), and the solution was degassed with argon for 10 min. To the abovesolution were added Xantphos (8.6 mg, 0.015 mmol) followed by Pd₂(dba)₃(14 mg, 0.015 mmol) and the solution was degassed again for 5 min withargon and stirred at 100° C. for 16h. After completion, ice water (5 mL)and dichloromethane (10 mL) were added to the reaction mixture andstirred for 30 min. A solid formed and was collected by filtration, andwashed with water (5 mL) followed by methanol (5 mL) to afford compoundI-17 (40 mg, 63% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ3.43-3.59 (m, 5H), 4.95 (t, J=5 Hz, 1H), 6.96 (t, J=4.8 Hz, 1H), 7.68(d, J=9 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J=9 Hz, 1H), 8.05 (d, J=9 Hz,1H), 8.17 (s, 1H), 8.58 (s, 1H), 9.09 (d, J=9 Hz, 1H), 10.92 (s, 1H). MSm/z (M+H): 411.2.

Example 74

Synthesis of(S)-3-((6-chloropyrimidin-4-yl)amino)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-22)

The title compound was synthesized in the same manner as 1-17substituting 6-chloropyrimidin-4-amine for 6-fluoropyrimidin-4-amine. toafford compound I-22 (20 mg) as a yellow solid. ¹H NMR (400 MHz,DMSO-D₆): δ: 3.43-3.59 (m, 5H), 4.95 (t, J=5 Hz, 1H), 6.96 (t, J=4.8 Hz,1H), 7.75 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.85 (s, 1H), 8.06 (d, J=9 Hz,1H), 8.46 (br s, 1H), 8.63 (s, 1H), 9.10 (d, J=9.3 Hz, 1H), 10.86 (s,1H). MS m/z (M+H): 427.37.

Example 75

Synthesis of(S)-2-chloro-4-((10-(hydroxymethyl)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)amino)pyrimidine-5-carboxamide(I-30)

To a solution of(S)-2-chloro-4-((10-(hydroxymethyl)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-3-yl)amino)-N-(4-methoxybenzyl)pyrimidine-5-carboxamide(INT-52) (22 mg, 0.04 mmol) in dichloromethane (2.0 mL) were addedtrifluoroacetic acid (0.5 mL, 0.04 mmol) followed bytrifluoromethanesulfonic acid (55.9 mg, 0.4 mmol) at 0° C. The resultingreaction mixture was stirred at room temperature for 1 h. Aftercompletion, the reaction mixture was concentrated under reduced pressureand co-distilled with dichloromethane (2×10 mL). The crude materialobtained was diluted with saturated sodium bicarbonate solution (10 mL)and stirred for 10 min. after which a precipitate formed. Theprecipitate was filtered and washed with water followed by 2% methanolin dichloromethane and dried to afford compound I-30 (11 mg, 52%) as abrown solid. ¹H NMR (400 MHz, DMSO-d₆): 3.42-3.50 (m, 3H), 3.55-3.58 (m,2H), 4.95 (br s, 1H), 7.04 (br s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.85 (brs, 1H), 8.07-8.09 (m, 2H), 8.52 (s, 1H), 8.61 (d, J=9.3 Hz, 1H), 8.90(s, 1H), 9.25 (d, J=9.5 Hz, 1H), 12.12 (s, 1H). MS m/z (M+H): 470.2.

Example 76

Synthesis of(R)-0-(aminomethyl)-3-((6-fluoropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(S8-6, I-26)

To a stirred solution of (S)-tert-butyl((3-(6-fluoropyrimidin-4-yl)amino)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-10-yl)methyl)carbamate(S8-5) (16.0 mg, 0.03 mmol) in dichloromethane (2.0 mL) was addedtrifluoroacetic acid (1.1 mL) at room temperature. The resultingreaction mixture was stirred at room temperature for 1 h. Aftercompletion, the reaction mixture was concentrated under reducedpressure. The crude material was triturated with diethyl ether to affordthe trifluoroacetate salt of compound I-26 (14 mg) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 2.81-2.88 (m, 1H), 2.97-3.02 (m, 1H),3.78-3.80 (m, 1H), 3.80-3.88 (m, 2H), 7.05 (br s, 1H), 7.72 (d, J=9.3Hz, 1H), 7.83 (br s, 2H), 7.93 (d, J=8.9 Hz, 1H), 8.07-8.10 (m, 2H),8.17 (s, 1H), 8.59 (s, 1H), 9.07 (d, J=9.1 Hz, 1H), 10.94 (br s, 1H). MSm/z (M+H): 410.3.

Example 77

Synthesis of(R)-10-(aminomethyl)-3-((6-chloropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-28)

The title compound was synthesized in the same manner as 1-17substituting 6-chloropyrimidin-4-amine for 6-fluoropyrimidin-4-amine and(R)-10-(aminomethyl)-3-chloro-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-47) for(S)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1) to afford compound I-28 as an orange solid. ¹H NMR (400 MHz,DMSO-d₆): δ 2.79-2.80 (m, 1H), 2.98-3.01 (m, 2H), 3.07-3.10 (m, 1H),3.69-3.79 (m, 2H), 3.82-3.88 (m, 1H), 7.78-7.88 (m, 3H), 8.08-8.10 (m,2H), 8.45 (br s, 1H), 8.64 (s, 1H), 9.08 (d, J=9.1 Hz, 1H), 10.89 (br s,1H). MS m/z (M+H): 426.3.

Example 78

Synthesis of(S)-10-((dimethylamino)methyl)-3-((6-fluoropyrimidin-4-yl)amino)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-31)

The title compound was synthesized in the same manner as 1-17substituting(S)-3-chloro-10-((dimethylamino)methyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-48) for(S)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1), to afford compound I-31 (6.0 mg, 40%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d): δ 2.25 (s, 3H), 2.52-2.54 (m, 2H), 3.22-3.25 (m, 1H),3.32-3.35 (m, 1H), 3.55-3.60 (m, 1H), 7.14 (t, J=5.6 Hz, 1H), 7.70 (d,J=9.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.23 (brs, 1H), 9.24 (d, J=9.2 Hz, 1H). MS m/z (M+H): 347.1.

Example 79

Synthesis of(R)-3-((6-fluoropyrimidin-4-yl)amino)-10-((methylamino)methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-35)

The title compound was synthesized in the same manner as 1-17substituting(R)-3-chloro-10-((methylamino)methyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-50) for(S)-3-chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(INT-1) to afford compound I-35 (17 mg, 14%) as a light brown solid. ¹HNMR (400 MHz, DMSO-d₆): δ 2.26 (s, 3H), 2.31-2.33 (m, 1H), 2.40-2.50 (m,1H), 3.22-3.25 (m, 1H), 3.55 (m, 2H), 7.05 (m, 1H), 7.69 (d, J=9.0 Hz,1H), 7.90 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.9 Hz, 1H), 8.17 (d, J=9.5 Hz,2H), 8.58 (s, 1H), 9.14 (d, J=9.1 Hz, 1H), 10.9 (br s, 1H). MS m/z(M+H): 424.2.

Example 80

Synthesis of(R)-3-((5-((tert-butyl(methyl)amino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-80)

To a stirred suspension of INT-6 (75 mg, 0.2 mmol) in anhydrous DMF (5mL) was added t-BuOK (28.1 mg, 0.25 mmol) at 0° C. to give a brownsolution. The resulting solution was stirred for further 0.5 h at thistemperature. INT-90 (93.2 mg, 0.4 mmol) in DMF (2 mL) was added dropwiseto the above solution and stirred overnight at room temperature. Thereaction mixture was partitioned between ethyl acetate (20 mL) and water(30 mL), the organic layer was separated and the aqueous layer wasextracted with ethyl acetate (2×20 mL). The combined organic layer waswashed with brine (50 mL) and the organic layer was separated, driedover Na₂SO₄, filtered and concentrated under reduced pressure.Purification by prep-HPLC afforded the desired product I-80 (24 mg, 18%)as a yellow solid. (400 MHz, DMSO-d6): δ 9.34 (d, J=9.2 Hz, 1H), 8.70(s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.03 (br, 1H), 7.82 (d, J=9.2 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 7.10-7.11 (m, 1H), 3.66 (s, 2H), 3.61 (br, 1H),3.46 (br, 2H), 2.17 (s, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.10 (s, 9H). MSm/z (M+H): 511.3.

Example 81

To a 100 mL round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was dissolved INT-6 (115.9 mg, 0.39 mmol) in DMF(10 mL). t-BuOK (1M in THF) (0.64 mL, 0.64 mmol) was added slowly viasyringe to the solution at 0° C. and the reaction changed to clearbrown. The resulting solution was stirred for 20 min at 0° C. After this20 min, INT-64 (137 mg, 0.58 mmol) in DMF (2 mL) was added dropwise withstirring at 0° C. The resulting solution was warmed to room temperatureand stirred overnight. LCMS confirmed the formation of the desiredproduct. The reaction was concentrated to dryness and the residue wasdiluted with EtOAc (300 mL) and washed with 2×300 ml water then 1×300 mlsaturated brine solution. The organic extract were then dried oversodium sulfate, filtered and concentrated to dryness. The crude materialwas then purified by column chromatography (DCM:MeOH=30:1). The desiredfractions were concentrated to dryness in vacuo and further purified byPrep HPLC to obtain (I-81) (536.7 mg, 28.5%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d6): δ 9.37 (d, J=9.2 Hz, 1H), 8.72 (s, 1H), 8.20 (d,J=9.2 Hz, 1H), 8.15 (d, J=4.4 Hz, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.63 (d,J=8.8 Hz, 1H), 7.19-7.16 (m, 1H), 4.71 (s, 2H), 3.73-3.71 (m, 2H),3.63-3.61 (m, 1H), 3.55-3.54 (m, 2H), 3.51-3.44 (m, 2H), 3.28 (s, 3H),1.20 (d, J=6.8 Hz, 3H). MS m/z (M+H): 500.0.

Example 82

Synthesis of(R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-82)

To a solution INT-6 (270 mg, 0.9 mmol) in DMA (or DMF) (3.0 mL) wasadded potassium tert-butoxide (202.4 mg, 1.8 mmol) at 0° C. and stirredfor 10 min. To the resulting mixture, INT-60 (280.1 mg, 1.4 mmol) wasadded at 0° C. The resulting reaction mixture was stirred at 25° C. for30 min. After completion, the reaction mixture was diluted with water(20.0 mL), whereupon a solid formed. The solid was filtered and driedunder vacuum yielding 250 mg. The crude was purified by reverse phaseprep-HPLC (10-95% MeCN/Water, 0.1% TFA) to afford I-82 (80 mg, 19%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (d, J=9.2 Hz, 1H), 8.70(br, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.11 (d, J=4.0 Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.14 (t, J=4.8 Hz, 1H), 4.64 (s, 2H),3.60-3.64 (m, 2H), 3.58 (br, 1H), 1.17-1.20 (m, 6H). MS m/z (M+H):470.5.

Example 83

Synthesis of((10R)-3-((5-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-83)

To a stirred suspension of INT-6 (130 mg, 0.43 mmol) in anhydrous DMF(15 mL) was added t-BuOK (1M in THF, 0.87 mL, 0.87 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor 0.5 h at this temperature. I-75 (110 mg, 0.45 mmol) in DMF (3 mL)was added dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(50 mL) and water (20 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with brine (30 mL) and the organic layerwas separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by prep-HPLC afforded the desired productI-83 (57.7 mg, 26.5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.36 (d, J=9.2 Hz, 1H), 8.64 (s, 1H), 8.20-8.14 (m, 2H), 7.85 (d, J=9.2Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.18-7.16 (m, 1H), 3.77 (s, 2H),3.63-3.43 (m, 3H), 2.98 (d, J=8.4 Hz, 2H), 2.46 (d, J=8.0 Hz, 2H),1.40-1.38 (m, 2H), 1.20 (d, J=6.8 Hz, 3H), 0.68-0.65 (m, 1H), 0.36-0.29(m, 1H).

Example 84

Synthesis of((R)-3-((2-chloro-5-((((S)-tetrahydrofuran-3-yl)oxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-84)

To a stirred solution of INT-6 (207 mg, 0.690 mmol) in DMF (15 mL) wasadded t-BuOK (155.19 mg, 1.38 mmol) at 0° C. and the reaction wasstirred for 10 min. Then a solution of INT-66 (189.47 mg, 0.76 mmol) inDMF (5 mL) was added at 0° C. and the reaction was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate (50 mL) and water (20 mL), the organic layer was separatedand the aqueous layer was extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with brine (30 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by prep-HPLC afforded the desired productI-84 (63.3 mg, 18%) as yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.34(d, J=8.0 Hz, 1H), 8.71 (s, 1H), 8.19-8.12 (m, 2H), 7.84 (d, J=8.8 Hz,1H), 7.61 (d, J=8.8 Hz, 1H), 7.16-7.14 (m, 1H), 4.70-4.63 (m, 2H),4.36-4.32 (m, 1H), 3.80-3.77 (m, 2H), 3.75-3.67 (m, 2H), 3.61-3.60 (m,1H), 3.47-3.46 (m, 2H), 2.02-1.97 (m, 2H), 1.22-1.17 (m, 3H). MS m/z(M+H): 511.9.

Example 85

Synthesis of(R)-3-((5-((3-azabicyclo[3.1.1]heptan-3-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-85)

To a stirred suspension INT-6 (100 mg, 0.33 mmol) in anhydrous DMF (10mL), was added t-BuOK (1M in THF, 0.67 mL, 0.67 mmol) at 0° C. to give abrown solution. The resulting solution was stirred for 0.5 h at thistemperature. INT-76 (110 mg, 0.40 mmol) in DMF (3 mL) was added dropwiseto the above solution and stirred overnight at room temperature. Thereaction mixture was partitioned between ethyl acetate (50 mL) and water(20 mL), the organic layer was separated and the aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organic layer waswashed with brine (30 mL) and the organic layer was separated, driedover Na₂SO₄, filtered and concentrated under reduced pressure.Purification by prep-HPLC afforded the desired product I-85 (43.7 mg,24.7%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (d, J=9.2 Hz,1H), 8.73 (s, 1H), 8.19-8.13 (m, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.18-7.15 (m, 1H), 3.84 (s, 2H), 3.62-3.42 (m, 3H), 2.91(s, 4H), 2.32-2.30 (m, 2H), 1.97-1.92 (m, 2H), 1.50-1.46 (m, 2H), 1.22(d, J=11.2 Hz, 3H).

Example 86

Synthesis of(R)-3-((2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-86)

In a 20 mL vial, INT-6 (0.05 g, 0.167 mmol) was added to 3 mL of dry DMFand sonicated briefly. To this, K₂CO₃ (0.231 g, 1.670 mmol) was addedand the reaction was warmed to 90° C. for 10 min. The reaction was thencooled to room temperature and2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (0.055 g, 0.288 mmol) wasadded and subsequently warmed to 90° C. for 2 h. Upon completion, thereaction was cooled, filtered to remove any undissolved potassiumcarbonate and the crude reaction mixture was directly purified byreverse phase prep-HPLC (10-95% MeCN/Water, 0.1% TFA) to yield I-86(0.052 g, 0.114 mmol, 68% yield) as a yellow solid after lyophilization.¹H NMR (400 MHz, DMSO-d6): δ 9.31 (d, J=9.2 Hz, 1H), 8.13 (d, J=8.7 Hz,1H), 8.10 (d, J=4.6 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=9.2 Hz,1H), 7.11 (br, 1H), 4.98 (s, 4H), 3.55 (m, 1H), 3.39 (m, 2H), 1.12 (d,J=6.9 Hz, 3H) MS m/z (M+H): 453.8.

Example 87

Synthesis of(R)-3(2-chloro-5-((diisopropylamino)methyl)pyrmidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-87)

To a suspension of INT-6 (128 mg, 0.429 mmol) in DMF (3 mL) at room tempwas added sodium hydride (60% in oil) (20.59 mg, 0.515 mmol). Thereaction color changed from yellow-green to dark brown and within 10 minthe reaction became homogeneous. After 20 min, the reaction mixture wascooled to 0° C. and a solution of INT-89 (135 mg, 0.515 mmol) in DMF(1.5 mL) was added dropwise over 2 min. The reaction was stirredovernight and the next morning the reaction was cooled to 0° C.,quenched with sat aq NH₄Cl (˜1 mL, initially dropwise, caution: gasevolution) and water ˜3 mL. The cooling bath was removed, and stirringwas continued at RT for 10 min to give yellow suspension. The reactionwas extracted with DCM (5×10 mL), an emulsion was persistent. Theorganic extracts were filtered through Na₂SO₄ and concentrated. Thecrude product was purified by prep HPLC (10-95% MeCN/Water, 0.1% TFA).I-87 (133 mg, 0.253 mmol, 59.0% yield) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J=9.2 Hz, 1H), 8.88 (br, 2H), 8.17(d, J=9.2 Hz, 1H), 8.13 (d, J=4.6 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.63(d, J=9.2 Hz, 1H), 7.14 (br, 1H), 4.51 (d, J=5.0 Hz, 2H) 3.82 (m, 2H),3.57 (m, 1H), 3.42 (m, 2H), 1.40 (d, J=6.4 Hz, 6H), 1.34 (d, J=6.4 Hz,6H), 1.14 (d, J=6.9 Hz, 3H). MS m/z (M+H):524.8.

Example 88

Synthesis of(R)-3-((2-chloro-5-((diisobutylamino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-88)

To a stirred suspension of INT-6 (31.3 mg, 0.1 mmol) in anhydrous DMF (4mL) was added t-BuOK (1 M in THF, 0.2 mL, 0.2 mmol) at 0° C. dropwise togive a brown solution and the resulting solution was stirred for further0.5 h at this temperature. INT-77 (60.2 mg, 0.2 mmol) in DMF (1 mL) wasadded dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(5 mL) and water (5 mL), the organic layer was separated and the aqueouslayer was extracted with ethyl acetate (2×5 mL). The combined organiclayer was washed with brine (10 mL) and the organic layer was separated,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative HPLC afforded I-88 (8.5 mg, 13.8%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (d, J=9.2 Hz, 1H), 8.72(s, 1H), 8.19-8.15 (m, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.55 (d, J=9.2 Hz,1H), 7.17-7.15 (m, 1H), 3.66-3.61 (m, 3H), 3.61-3.48 (m, 2H), 2.19-2.17(m, 4H), 1.84-1.77 (m, 1H), 1.23-1.18 (m, 3H), 0.86-0.82 (m, 12H). MSm/z (M+H): 553.1.

Example 89

Synthesis of(10R)-3-((2-chloro-5-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-t]quinolin-8-one(I-89)

To a stirred suspension of INT-6 (100 mg, 0.3 mmol) in anhydrous DMF (10mL) was added t-BuOK (1 M in THF, 0.7 mL, 0.7 mmol) at 0° C., dropwise,to give a brown solution. The resulting solution was stirred for further10 min at room temperature. INT-78 (184 mg, 0.6 mmol) in DMF (2 mL) wasadded dropwise to the above solution and stirred 4 h at roomtemperature. The reaction mixture was partitioned between ethyl acetate(30 mL) and water (40 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with brine (80 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-89 (72.5 mg,38.6%) as a 1:1 mixture of diastereomers. ¹H NMR (400 MHz, DMSO-d6) δ9.35 (d, J=9.1 Hz, 1H), 8.70 (s, 1H), 8.25-8.09 (m, 2H), 7.84 (d, J=8.8Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.16 (t, J=5.2 Hz, 1H), 4.17 (d, J=14.8Hz, 1H), 3.70-3.55 (m, 2H), 3.52-3.34 (m, 3H), 3.30-3.17 (m, 4H),3.10-2.95 (m, 1H), 2.90-2.75 (m, 1H), 2.50-2.25 (m, 1H), 2.00-1.80 (m,1H), 1.75-1.59 (m, 2H), 1.57-1.40 (m, 1H), 1.19 (d, J=6.8 Hz, 3H) MS m/z(M+H): 539.2.

Example 90

Synthesis of(R)-3-((2-chloro-5-(((2-methoxyethyl)(methyl)amino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-90)

To a stirred suspension of INT-6 (72 mg, 0.24 mmol) in anhydrous DMF (5mL) was added t-BuOK (1 M in THF, 0.48 mL, 0.48 mmol) at 0° C. dropwiseto give a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-79 (120 mg, 0.48 mmol) in DMF (1 mL) wasadded dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(20 mL) and water (30 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×20 mL). The combinedorganic layer was washed with brine (50 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-90 (36.9 mg,28.4%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d) δ 9.35 (d, J=9.0 Hz,1H), 8.71 (s, 1H), 8.19-8.13 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.60 (d,J=9.0 Hz, 1H), 7.17-7.13 (m, 1H), 3.71 (s, 2H), 3.51-3.49 (m, 1H),3.48-3.46 (m, 4H), 3.23 (s, 3H), 2.74-2.59 (m, 2H), 2.30 (s, 3H), 1.19(d, J=6.6 Hz, 3H). MS m/z (M+H): 513.0.

Example 91

Synthesis of(R)-3-((2-chloro-5((isopropyl(methyl)amino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-91)

To a stirred suspension of INT-6 (39.9 mg, 0.13 mmol) in anhydrous DMF(4 mL) was added t-BuOK (1M in THF, 0.26 mL, 0.26 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-70 (62 mg, 0.26 mmol) in DMF(1 mL) was added dropwise to the above solution and stirred overnight atroom temperature. The reaction mixture was partitioned between ethylacetate (5 mL) and water (5 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×5 mL). The combinedorganic layers were washed with brine (10 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-91 (19 mg, 29%) asa yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.36 (d, J=9.2 Hz, 1H),8.68 (s, 1H), 8.19-8.14 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.60 (d, J=9.2Hz, 1H), 7.17-7.15 (m, 1H), 3.65-3.61 (m, 3H), 3.48-3.46 (m, 2H),2.94-2.87 (m, 1H), 2.18 (s, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.4Hz, 6H). MS m/z (M+H): 497.0.

Example 92

Synthesis of(R)-3-((2-chloro-5-((cylcohexyl(methyl)amino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-92)

To a stirred suspension of INT-6 (198 mg, 0.66 mmol) in anhydrous DMF(15 mL) was added t-BuOK (1 M in THF, 1.3 mL, 1.32 mmol) at 0° C.dropwise to give a brown solution and the resulting solution was stirredfor further 0.5 h at this temperature. INT-72 (199.5 mg, 0.73 mmol) inDMF (5 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (20 mL) and water (30 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×20mL). The combined organic layer was washed with brine (50 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded the desired product I-92 (19.4 mg, 9.7%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 9.35 (d, J=8.0 Hz, 1H), 8.67 (s, 1H),8.19-8.14 (m, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H),7.18-7.15 (m, 1H), 3.71 (s, 2H), 3.62-3.61 (m, 1H), 3.48-3.47 (m, 2H),2.46-2.44 (m, 1H), 2.24 (s, 3H), 1.81-1.71 (m, 4H), 1.32-1.15 (m, 9H).MS m/z (M+H): 537.4.

Example 93

Synthesis of(R)-3-((2-chloro-5-((4-methoxypiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-93)

To a stirred suspension of INT-6 (90 mg, 0.3 mmol) in anhydrous DMF (9mL) was added t-BuOK (1 M in THF, 0.6 mL, 0.6 mmol) at 0° C. dropwise togive a brown solution and the resulting solution was stirred for further0.5 h at this temperature. INT-73 (166.1 mg, 0.6 mmol) in DMF (2 mL) wasadded dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(30 mL) and water (40 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with brine (80 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-93 (43.5 mg,26.2%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (d, J=9.0 Hz,1H), 8.69 (s, 1H), 8.19-8.14 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.60 (d,J=9.0 Hz, 1H), 7.18-7.15 (m, 1H), 3.64 (s, 3H), 3.61-3.46 (m, 2H),3.22-3.15 (m, 4H), 2.77-2.75 (m, 2H), 2.27-2.20 (m, 2H), 1.86-1.72 (m,2H), 1.51-1.40 (m, 2H), 1.20 (d, J=6.6 Hz, 3H). MS m/z (M+H): 539.0.

Example 94

Synthesis of(R)-3-((2-chloro-5-((4-ethylpiperazin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-94)

To a stirred suspension of INT-6 (80 mg, 0.27 mmol) in anhydrous DMF (8mL) was added t-BuOK (1M in THF, 0.54 mL, 0.54 mmol) at 0° C. dropwiseto give a brown solution and the resulting solution was stirred forfurther 0.5 h at this temperature. INT-74 (147.1 mg, 0.54 mmol) in DMF(2 mL) was added dropwise to the above solution and stirred overnight atroom temperature. The reaction mixture was partitioned between ethylacetate (30 mL) and water (40 mL), the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×30 mL). Thecombined organic layers were washed with brine (80 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by preparative HPLC afforded I-94 (38.9mg, 26.7%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (d, J=9.0Hz, 1H), 8.69 (s, 1H), 8.20-8.14 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.61(d, J=9.0 Hz, 1H), 7.18-7.16 (m, 1H), 3.66-3.62 (m, 2H), 3.47-3.45 (m,2H), 2.49-2.27 (m, 10H), 1.19 (d, J=6.6 Hz, 3H), 0.99 (br s, 3H). MS m/z(M+H): 538.1.

Example 95

Synthesis of(R)-3-((2-chloro-5-((3,3-dimethylpiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-95)

To a stirred suspension of INT-6 (115 mg, 0.38 mmol) in anhydrous DMF(15 mL) was added t-BuOK (1 M in THF, 0.76 mL, 0.76 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-80 (115.8 mg, 0.42 mmol) inDMF (5 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (30 mL) and water (40 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×30mL). The combined organic layers were washed with brine (80 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-95 (33.5 mg, 29.1%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.33 (d, J=9.2 Hz, 1H), 8.67 (s, 1H), 8.17-8.12 (m, 2H),7.82 (d, J=8.8 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.15-7.13 (m, 1H),3.60-3.58 (m, 3H), 3.58-3.41 (m, 2H), 2.39-2.31 (m, 2H), 2.14-2.06 (m,2H), 1.56-1.52 (m, 2H), 1.20-1.13 (m, 5H), 0.90 (s, 6H). MS m/z (M+H):537.0.

Example 96

Synthesis of(R)-3-((2-chloro-5-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-96)

To a stirred suspension of INT-6 (203.3 mg, 0.68 mmol) in anhydrous DMF(17 mL) was added t-BuOK (1 M in THF, 1.36 mL, 1.36 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-63 (262.2 mg, 1.36 mmol) inDMF (3 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (40 mL) and water (50 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×40mL). The combined organic layers were washed with brine (80 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-96 (110.4 mg, 35.5%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 9.37 (d, J=9.2 Hz, 1H), 8.72 (s, 1H), 8.19 (d, J=8.8 Hz, 1H),8.14 (d, J=4.4 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H),7.18-7.16 (m, 1H), 4.62 (s, 2H), 3.62-3.61 (m, 1H), 3.51-3.47 (m, 2H),3.42 (s, 3H), 1.19 (d, J=6.8 Hz, 3H). MS m/z (M+H): 455.9.

Example 97

Synthesis of(R)-3-((5-(tert-butoxymethyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-97)

To a stirred solution of INT-6 (100 mg, 0.3 mmol) in DMF (10 mL) wasadded t-BuOK (1 M in THF, 0.7 mL, 0.7 mmol) at 0° C. dropwise to give abrown solution that was stirred for 10 min. INT-56 (157 mg, 0.7 mmol) inDMF (2 mL) was added dropwise to the above solution and stirred for 2 hat room temperature. The reaction mixture was partitioned between ethylacetate (50 mL) and water (50 mL), the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (100 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by preparative HPLC afforded I-97 (70.4mg, 42.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (d, J=9.2Hz, 1H), 8.69 (s, 1H), 8.21-8.10 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.61(d, J=9.2 Hz, 1H), 7.17-7.14 (m, 1H), 4.59 (s, 2H), 3.70-3.55 (m, 1H),3.54-3.38 (m, 2H), 1.25 (s, 9H), 1.18 (d, J=6.8 Hz, 3H). MS m/z (M+H):498.1.

Example 98

Synthesis of(R)-3-((2-chloro-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4-]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-98)

To a stirred suspension of INT-6 (170 mg, 0.57 mmol) in anhydrous DMF(17 mL) was added t-BuOK (I M in THF, 1.14 mL, 1.14 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-7 (179.3 mg, 0.68 mmol) inDMF (2 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (40 mL) and water (50 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×40mL). The combined organic layers were washed with brine (80 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-98 (78.9 mg, 26.1%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.37 (d, J=9.0 Hz, 1H), 8.75 (s, 1H), 8.20-8.14 (m, 2H), 7.86(d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.18-7.16 (m, 1H), 4.73 (s,2H), 3.86-3.81 (m, 2H), 3.74-3.70 (m, 1H), 3.63-3.61 (m, 1H), 3.49-3.47(m, 2H), 3.38-3.34 (m, 2H), 1.96-1.92 (m, 2H), 1.55-1.46 (m, 2H), 1.20(d, J=6.6 Hz, 3H). MS m/z (M+H): 526.2.

Example 99

Synthesis of(R)-3-((2-chloro-5-(((R)-2-methylpyrrolidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-99)

To a stirred solution of INT-6 (100 mg, 0.3 mmol) in DMF (10 mL) wereadded t-BuOK (1M in THF, 0.7 mL, 0.7 mmol) at 0° C. dropwise to give abrown solution and the reaction was stirred for 10 min. INT-81 (90 mg,0.4 mmol) in DMF (2 mL) was added dropwise to the above solution and thereaction was stirred 4 h at room temperature. The reaction mixture waspartitioned between ethyl acetate (20 mL) and water (50 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic layers were washed with brine(80 mL) and the organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification by preparativeHPLC afforded I-99 (16.5 mg, 9.3%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.33 (d, J=9.1 Hz, 1H), 8.67 (s, 1H), 8.23-8.09 (m, 2H), 7.83(d, J=9.2 Hz, 1H), 7.68-7.55 (m, 1H), 7.20-7.10 (m, 1H), 4.02 (d, J=14.8Hz, 1H), 3.70-3.55 (m, 1H), 3.54-3.38 (m, 3H), 3.05-2.90 (m, 1H),2.56-2.50 (m, 1H), 2.30-2.15 (m, 1H), 2.00-1.85 (m, 1H), 1.70-1.55 (m,2H), 1.40-1.22 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H)MS m/z (M+H): 509.1.

Example 100

Synthesis of(R)-3-((2-chloro-5-((2-fluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-100)

To a stirred suspension of INT-6 (444 mg, 1.48 mmol) in anhydrous DMF(40 mL) was added t-BuOK (1M in THF, 3 mL, 3 mmol) at 0° C. dropwise togive a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-65 (400.6 mg, 1.8 mmol) in DMF (2 mL) wasadded dropwise to the above solution and the reaction was stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (60 mL) and water (40 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×30mL). The combined organic layers were washed with brine (60 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-100 (187.5 mg, 25.9%) as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.37 (d, J=9.0 Hz, 1H), 8.74 (s, 1H), 8.21-8.11 (m, 2H), 7.86(d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.18-7.14 (m, 1H), 4.75 (s,2H), 4.70 (t, J=3.9 Hz, 1H), 4.54 (t, J=3.9 Hz, 1H), 3.90 (t, J=3.9 Hz,1H), 3.80 (t, J=3.9 Hz, 1H), 3.62-3.46 (m, 3H), 1.19 (d, J=6.6 Hz, 3H).MS m/z (M+H): 488.0.

Example 101

Synthesis of(R)-3-((2-chloro-5-(((S)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-101)

To a stirred solution of INT-6 (100 mg, 0.3 mmol) in DMF (10 mL) wasadded t-BuOK (1M in THF, 0.7 mL, 0.7 mmol) at 0° C. dropwise to give abrown solution and the reaction was stirred for 10 min. INT-82 (164 mg,0.6 mmol) in DMF (2 mL) was added dropwise to the above solution andstirred 4 h at room temperature. The reaction mixture was partitionedbetween ethyl acetate (20 mL) and water (40 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×20mL). The combined organic layers were washed with brine (100 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-101 (32.0 mg, 18.1%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.33 (d, J=9.1 Hz, 1H), 8.67 (s, 1H), 8.23-8.09 (m, 2H), 7.83(d, J=8.8 Hz, 1H), 7.68-7.55 (m, 1H), 7.20-7.10 (m, 1H), 4.02 (d, J=14.4Hz, 1H), 3.68-3.55 (m, 1H), 3.54-3.37 (m, 3H), 3.05-2.90 (m, 1H),2.56-2.50 (m, 1H), 2.30-2.15 (m, 1H), 2.00-1.85 (m, 1H), 1.71-1.55 (m,2H), 1.40-1.22 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H)MS m/z (M+H): 509.1.

Example 102

Synthesis of(R)-3-((5-((tert-butylamino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-102)

To a suspension of INT-6 (77 mg, 0.256 mmol) in DMF (5 mL) at roomtemperature was added potassium carbonate (283 mg, 2.050 mmol). Themixture was degassed by evacuation and refill with N₂ (3×). The mixturewas heated to 90° C. for 10 min, and then a solution of INT-88 (78 mg,0.333 mmol) in DMF (2 mL) was added via syringe. After 1 h at 90° C. thereaction was complete. The reaction mixture was filtered and dilutedwith water and the entire reaction mass was purified directly by reversephase preparative HPLC (10-95% MeCN/Water, 0.1% TFA) to give I-102 (136mg, 0.223 mmol, 87% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.41 (d, J=9.2 Hz, 1H), 8.96 (br, 2H), 8.85 (s, 1H), 8.23 (d, J=8.7Hz, 1H), 8.18 (d, J=4.6 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.64 (d, J=9.2Hz, 1H), 7.18 (br, 1H), 4.36 (br, 2H) 3.80-3.48 (m, 4H), 1.42 (s, 9H),1.19 (d, J=6.9 Hz, 3H). MS m/z (M+H): 497.1.

Example 103

Synthesis of(R)-3-((2-chloro-5-(((3-methyloxetan-3-yl)oxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-103)

To a stirred suspension of INT-6 (251 mg, 0.84 mmol) in anhydrous DMF(15 mL) was added t-BuOK (1M in THF, 1.68 mL, 1.68 mmol) at 0° C.dropwise to give a brown solution and the resulting solution was stirredfor further 0.5 h at this temperature. INT-61 (190 mg, 0.76 mmol) in DMF(5 mL) was added dropwise to the above solution and stirred overnight atroom temperature. The reaction mixture was partitioned between ethylacetate (30 mL) and water (40 mL), the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×30 mL). Thecombined organic layers were washed with brine (80 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by preparative HPLC afforded I-103 (53.1mg, 27.9%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.37 (d,J=9.0 Hz, 1H), 8.79 (s, 1H), 8.21-8.13 (m, 2H), 7.87 (d, J=9.0 Hz, H),7.64 (d, J=9.0 Hz, 1H), 7.18-7.15 (m, 1H), 4.67-4.65 (m, 4H), 4.37 (d,J=6.0 Hz, 2H), 3.62-3.61 (m, 1H), 3.47-3.46 (m, 2H), 1.59 (s, 3H),1.24-1.18 (m, 3H). MS m/z (M+H): 512.1.

Example 104

Synthesis of(R)-3-((5-((tert-butyl(methyl)amino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-104)

To a stirred solution of INT-6 (100 mg, 0.3 mmol) in DMF (10 mL) wereadded NaH (33 mg, 0.8 mmol) at 0° C. and was stirred for 2h. INT-58 (86mg, 0.4 mmol) in DMF (2 mL) was added dropwise to the above solution andthen heated to 135° C. for 70 min under microwave irradiation. Thereaction mixture was cooled and partitioned between ethyl acetate (50mL) and water (40 mL), the organic layer was separated and the aqueouslayer was extracted with ethyl acetate (2×50 mL). The combined organiclayers were washed with brine (80 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by reverse phasepreparative HPLC (10-95% McCN/Water, 0.1% TFA) afforded I-104 (21.4 mg,13.3%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=9.2 Hz,1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.20-8.09 (m, 2H), 7.78 (d, J=8.8 Hz,1H), 7.49 (d, J=9.2 Hz, 1H), 7.13-7.11 (m, 1H), 3.70-3.52 (m, 3H),3.50-3.38 (s, 2H), 2.25-2.13 (m, 5H), 1.90-1.75 (m, 1H), 1.18 (d, J=6.8Hz, 3H), 0.85 (d, J=6.4 Hz, 6H). MS m/z (M+H): 477.2.

Example 105

Synthesis of(R)-3-((2-chloro-6,6-dioxido-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-105)

INT-6 (50 mg, 0.167 mmol) was suspended in 10 mL of dry DMF and thevessel was flushed with nitrogen. Potassium carbonate was added (0.231g, 1.670 mmol) and the reaction was warmed to 90° C. for 10 min. To thismixture, 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine6,6-dioxide (51 mg, 0.200 mmol) was added and the reaction was stirredan additional 1 hour at 90° C. The reaction was judged complete byLC/MS, poured into saturated NH₄Cl (aq.) and extracted 3× with DCM. Thecombined DCM was dried over sodium sulfate, filtered and concentrated.The crude material was then purified by reverse phase HPLC to affordI-105 (4 mg, 7.75 μmol, 4.64% yield). ¹H NMR (400 MHz, DMSO-d6): δ 9.31(d, J=9.2 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.09 (d, J=4.5 Hz, 1H), 7.80(d, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 3.62 (t, J=6.9 Hz, 2H), 3.57(m, 1H), 3.38 (m, 4H), 1.12 (d, J=6.9 Hz, 3H). MS m/z (M+H): 516.0.

Example 106

Synthesis of(R)-3-((2-chloro-5-(((S)-3-methoxypiperidin-1-yl)methyl)pyrmidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-106)

To a stirred suspension of INT-6 (90 mg, 0.3 mmol) in anhydrous DMF (9mL) was added t-BuOK (1M in THF, 0.6 mL, 0.6 mmol) at 0° C. dropwise togive a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-85(166 mg, 0.6 mnmol) in DMF (2 mL) wasadded dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(30 mL) and water (40 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with brine (80 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-106 (4.0 mg, 2.5%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (d, J=9.2 Hz, 1H),8.67 (s, 1H), 8.17-8.12 (m, 2H), 7.82 (d, J=8.8 Hz, 1H), 7.58 (d, J=9.2Hz, 1H), 7.16-7.14 (m, 1H), 3.66-3.52 (m, 3H), 3.47-3.44 (m, 2H),3.23-3.20 (m, 4H), 2.98-2.95 (m, 1H), 2.70-2.67 (m, 1H), 2.11-2.06 (m,1H), 2.01-1.96 (m, 1H), 1.86-1.89 (m, 1H), 1.67-1.62 (m, 1H), 1.45-1.36(m, 1H), 1.21-1.12 (m, 4H). MS m/z (M+H): 539.2.

Example 107

Synthesis of(R)-3-((2-chloro-5-(((R)-3-methoxypiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-107)

To a stirred suspension of INT-6 (90 mg, 0.3 mmol) in anhydrous DMF (9mL) was added t-BuOK (1M in THF, 0.6 mL, 0.6 mmol) at 0° C. dropwise togive a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-86 (166 mg, 0.6 mmol) in DMF (2 mL) wasadded dropwise to the above solution and stirred overnight at roomtemperature. The reaction mixture was partitioned between ethyl acetate(30 mL) and water (40 mL), the organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with brine (80 mL) and the organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative HPLC afforded I-107 (56.3 mg,33.6%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d) δ 9.34 (d, J=9.2 Hz,1H), 8.68 (s, 1H), 8.17-8.12 (m, 2H), 7.82 (d, J=8.8 Hz, 1H), 7.58 (d,J=9.2 Hz, 1H), 7.16-7.14 (m, 1H), 3.66 (s, 1H), 3.62-3.57 (m, 3H),3.47-3.44 (m, 2H), 3.23-3.20 (m, 4H), 2.98-2.95 (m, 1H), 2.70-2.67 (m,1H), 2.11-2.06 (m, 1H), 2.01-1.96 (m, 1H), 1.86-1.89 (m, 1H), 1.67-1.62(m, 1H), 1.45-1.36 (m, 1H), 1.21-1.12 (m, 4H). MS m/z (M+H): 539.1.

Example 108

Synthesis of(R)-3-((2-chloro-5-(((2-ethoxyethyl)methyl)amino)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-108)

To a stirred suspension of INT-6 (400 mg, 1.34 mmol) in anhydrous DMF(35 mL) was added t-BuOK (1M in THF, 2.67 mL, 2.67 mmol) at 0° C. togive a brown solution. The resulting solution was stirred for anadditional 0.5 h at this temperature. INT-87 (271.4 mg, 1.34 mmol) inDMF (5 mL) was added dropwise to the above solution and the reaction wasstirred overnight at room temperature. The reaction mixture waspartitioned between ethyl acetate (30 mL) and water (40 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×30 mL). The combined organic layers were washed with brine(80 mL) and the organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification by preparativeHPLC afforded I-108 (36.9 mg, 13.6%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.33 (d, J=9.2 Hz, 1H), 8.17-8.11 (m, 2H), 7.83 (d, J=8.8Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.16-7.13 (m, 1H), 3.60-3.59 (m, 1H),3.50-3.40 (m, 2H), 2.80-2.79 (m, 2H), 2.74-2.71 (m, 2H), 1.84-1.83 (m,4H), 1.17 (d, J=9.2 Hz, 3H). MS m/z (M+H): 466.0.

Example 109

Synthesis of(R)-3-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-109)

To a stirred suspension of INT-6 (339 mg, 1.13 mmol) in anhydrous DMF(25 mL) was added t-BuOK (1M in THF, 2.26 mL, 2.26 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature.2,4-dichloro-5,6,7,8-tetrahydroquinazoline (299.1 mg, 1.13 mmol) in DMF(5 mL) was added dropwise to the above solution and the reaction wasstirred overnight at room temperature. The reaction mixture waspartitioned between ethyl acetate (30 mL) and water (40 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×30 mL). The combined organic layers were washed with brine(80 mL) and the organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification by preparativeHPLC afforded I-109 (87.4 mg, 29.2%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.34 (d, J=9.2 Hz, 1H), 8.71 (s, 1H), 8.18-8.11 (m, 2H),7.83 (d, J=9.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H). 7.10-7.20 (m, 1H), 3.70(s, 2H), 3.60-3.50 (m, 1H), 3.52-3.36 (m, 6H), 2.63-2.60 (m, 2H), 2.29(s, 3H), 1.17 (d, J=7.8 Hz, 3H), 1.06 (t, J=7.8 Hz, 3H). MS m/z (M+H):527.0.

Example 110

Synthesis of(R)-3-((2-chloro-5-((2,2-difluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-110)

To a stirred suspension of INT-6 (154.4 mg, 0.52 mmol) in anhydrous DMF(30 mL) was added t-BuOK (1 M in THF, 0.5 mL, 0.88 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-62 (150.4 mg, 0.62 mmol) inDMF (2 mL) was added dropwise to the above solution and the reaction wasstirred overnight at room temperature. The reaction mixture waspartitioned between ethyl acetate (20 mL) and water (30 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic layers were washed with brine(40 mL) and the organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification by preparativeHPLC afforded I-110 (70.0 mg, 26.8%) as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ 9.37 (br d, J=9.0 Hz, 1H), 8.74 (s, 1H), 8.19 (d, J=9.0 Hz,1H), 8.13 (d, J=4.2 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.62 (d, J=9.0 Hz,1H), 7.16 (br t, J=4.8 Hz, 1H), 6.45-6.42 (m, 1H), 4.82 (s, 2H),3.96-3.84 (m, 2H), 3.65-3.56 (m, 1H), 3.47 (t, J=4.5 Hz, 2H), 1.19 (d,J=6.6 Hz, 3H). MS m/z (M+H): 506.0.

Example 111

Synthesis of(R)-3-((2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidin-5-yl)methoxy)propanenitrile(i-111)

To a stirred suspension of INT-6 (120 mg, 0.4 mmol) in anhydrous DMF (12mL) was added t-BuOK (1M in THF, 0.8 mL, 0.8 mmol) at 0° C. dropwise togive a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-68 (186 mg, 0.8 mmol) in DMF (2 mL) wasadded dropwise to the above solution and the reaction stirred overnightat room temperature. The reaction mixture was partitioned between ethylacetate (30 mL) and water (40 mL), the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×30 mL). Thecombined organic layers were washed with brine (80 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by preparative HPLC afforded I-111 (55.9mg, 27.6%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (d, J=9.0Hz, 1H), 8.73 (s, 1H), 8.19-8.12 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.62(d, J=9.0 Hz, 1H), 7.16-7.14 (m, 1H), 4.75 (s, 2H), 3.77 (t, J=6.0 Hz,2H)), 3.60-3.59 (m, 1H), 3.49-3.45 (m, 2H), 2.88-2.85 (m, 2H), 1.18 (d,J=6.8 Hz, 3H). MS n/z (M+H): 495.1.

Example 112

Synthesis of(R)-3-((2-chloro-5-((methylsulfonyl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-112)

INT-6 (0.207 g, 0.692 mmol) was dissolved in 2 mL of dry DMF and K₂CO₃(0.956 g, 6.92 mmol) was added. The reaction was warmed to 90° C. for 5min, cooled and INT-54 (0.250 g, 1.038 mmol) in DMSO was added. Thereaction was stirred at 90° C. for 3 h at which time the reaction wasdetermined to be completed. The reaction was cooled and the excess basewas filtered away. The crude reaction mixture was purified by reversephase HPLC to give I-112 (0.105 g, 0.208 mmol, 30% yield). ¹H NMR (400MHz, DMSO-d₆): δ 9.34 (d, J=8.2 Hz, 1H), 8.75 (s, 1H), 8.18 (d, J=8.7Hz, 1H), 8.14 (d, J=2.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.58 (d, J=9.2Hz, 1H), 7.16 (t, J=5.5 Hz, 1H), 4.75 (s, 2H), 3.59 (m, 1H), 3.44 (m,2H), 3.17 (s, 3H), 1.16 (d, J=6.9 Hz, 3H). MS m/z (M+H): 504.0.

Example 113

Synthesis of(R)-3-((2-chloro-5-((difluoromethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-113)

To a stirred suspension of INT-6 (109.0 mg, 0.36 mmol) in anhydrous DMF(10 mL) was added t-BuOK (1M in THF, 0.62 mL, 0.62 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-55 (100.1 mg, 0.42 mmol) inDMF (2 mL) was added dropwise to the above solution and the reaction wasstirred overnight at room temperature. The reaction mixture waspartitioned between ethyl acetate (10 mL) and water (10 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×10 mL). The combined organic layers were washed with brine(10 mL) and the organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude was passed throughsilica gel (DCM/MeOH 30:1) to afford I-113 (13.4 mg, 7.48%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.34 (d, J=8.7 Hz, 1H), 8.78 (s,1H), 8.18-8.09 (m, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H),7.13-6.62 (m, 2H), 5.09 (s, 2H), 3.57-3.56 (m, 1H), 3.50-3.49 (m, 2H),1.15 (d, J=6.0 Hz, 3H). MS m/z (M+H): 492.2.

Example 114

Synthesis of(R)-3-((5-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-114)

To a stirred suspension of INT-6 (120.0 mg, 0.40 mmol) in anhydrous DMF(12 mL) was added t-BuOK (1M in THF, 0.8 mL, 0.8 mmol) at 0° C. dropwiseto give a brown solution. The resulting solution was stirred for further0.5 h at this temperature. INT-83 (131.9 mg, 0.48 mmol) in DMF (3 mL)was added dropwise to the above solution and the reaction stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (30 mL) and water (40 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×40mL). The combined organic layers were washed with brine (80 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by preparative HPLCafforded I-114 (40.9 mg, 19%) as a mixture of diastereomers. ¹H NMR (300MHz, DMSO-d₆) δ 9.31 (d, J=9.0 Hz, 1H), 8.80 (s, 1H), 8.15-8.08 (m, 2H),7.80 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.12-7.09 (m, 1H),3.58-3.54 (m, 5H), 3.45-3.39 (m, 4H), 3.11-3.09 (m, 2H), 1.94-1.90 (m,2H), 1.76-1.72 (m, 2H), 1.15 (d, J=6.6 Hz, 3H). MS m/z (M+H): 537.0.

Example 115

Synthesis of(R)-3-((2-chloro-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-115)

To a stirred solution of INT-6 (215.37 mg, 0.720 mmol) in DMF (30 mL)was added t-BuOK (1M in THF) (0.96 mL, 0.960 mmol) at 0° C. and thereaction was stirred at this temperature for 20 minutes to give a brownsolution. Then INT-84 (360 mg, 0.96 mmol) was added to the reactionmixture at 0° C., was warmed to room temperature and allowed to stirovernight. The reaction mixture was diluted with water, the aqueouslayer was extracted with ethyl acetate (3×50 ml) and the organic extractwas washed with 2×20 ml saturated brine solution. The organic layer wasdried over sodium sulfate, filtered and then concentrated. The crudematerial was filtered through silica gel eluting with ethyl acetate toobtain tert-butyl(2R,6S)-4-((2-chloro-4-(((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-3-yl)oxy)pyrimidin-5-yl)methyl)-2,6-dimethylpiperazine-1-carboxylate(180 mg, 29%) as a yellow solid. To this material (100.0 mg, 0.16 mmol)dissolved in DCM, TFA (1.0 mL, 0.16 mmol) was added and the reaction wasstirred at room temperature for 1 minutes. The mixture was quenched byaqueous saturated NaHCO₃ (10 mL) followed by extraction with ethylacetate (3×30 mL). The combined organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Furtherpurification by preparative TLC on silica gel (DCM:MeOH=4:1) affordedI-115 (67 mg, 65.5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35(d, J=9.0 Hz, 1H), 8.71 (s, 1H), 8.20-8.12 (m, 2H), 7.82 (d, J=8.8 Hz,1H), 7.58 (d, J=9.2 Hz, 1H), 7.16-7.14 (m, 1H), 3.66-3.52 (m, 3H),3.49-3.41 (m, 2H), 3.11-2.79 (m, 4H), 1.91-1.75 (m, 2H), 1.22-1.17 (m,4H), 1.02 (d, J=5.6 Hz, 6H). MS m/z (M+H): 538.1.

Example 116

Synthesis of(R)-3-((5-bromo-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-]quinolin-8-one(I-116)

INT-6 (1.6 g, 5.34 mmol) was suspended in 20 mL of dry DMF. K₂CO₃ (7.39g, 53.4 mmol) was added and the reaction was flushed with nitrogen. Thereaction was warmed to 90° C. for 10 minutes, cooled and5-bromo-2,4-dichloropyrimidine (1.583 g, 6.95 mmol) was added. Thereaction was warmed again to 90° C. for an additional 4 h. The reactionwas cooled, filtered to remove any undissolved base and then poured intowater (200 mL). The resulting precipitate was collected by filtrationand dried under reduced pressure to afford I-116 (1.922 g, 3.92 mmol,73.3% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.39 (d,J=9.6 Hz, 1H), 9.03 (s, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.16 (d, J=4.1 Hz,1H), 7.87 (d, J=9.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.18 (t, J=5.5 Hz,1H), 3.61 (m, 1H), 3.46 (m, 2H), 1.19 (d, J=6.9 Hz, 3H).

Example 117

Synthesis of(R)-3-((6-((tert-butylamino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-117)

t-Butyl amine (0.019 ml, 0.363 mmol), sodium iodide (0.272 g, 1.814mmol) and (R)-INT-93 (0.167 g, 0.363 mmol) were dissolved in 3 mL of dryDMF. The reaction was stirred at room temperature for 8 hours. Oncecomplete the reaction was filtered to remove excess salts and purifieddirectly by reverse phase preparative HPLC (10-95% MeCN/Water, 0.1% TFA)to give I-117. ¹H NMR (400 MHz, DMSO-d6): δ 9.40 (d, J=9.2 Hz, 1H), 9.10(t, J=6.0 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H), 8.16 (d, J=4.1 Hz, 1H), 7.82(d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.51 (s, 1H), 7.16 (m, 1H),4.39 (t, J=4.0 Hz, 2H), 3.59 (m, 1H), 3.44 (m, 2H), 1.33 (s, 91), 1.17(d, J=6.9 Hz). MS m/z (M+H): 484.1.

Example 118

Synthesis of(R)-3-((6-((tert-butyl(methyl)amino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-118)

I-117 (0.025 g, 0.050 mmol) and formaldehyde (37% aq) (0.011 ml, 0.151mmol) were dissolved in 3 mL THF, 1 mL MeOH and 0.1 mL acetic acid. Tothis mixture sodium triacetoxyborohydride (0.053 g, 0.252 mmol) wasadded. The reaction was stirred for 2 h at room temperature,concentrated to dryness and redissolved in 3 mL DMSO w/1 mL H₂O anddirectly purified by reverse phase preparative HPLC (10-95% MeCN/Water,0.1% TFA) to give I-118. ¹H NMR (400 MHz, DMSO-d6): δ 9.62 (br, 1H),9.40 (d, J=9.2 Hz, 1H), 8.20 (d, J=8.7 Hz), 8.16 (d, J=4.1 Hz, 1H), 7.83(d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.59 (s, 1H), 7.17 (br, 1H),4.69 (d, J=15.1 Hz, 1H), 4.27 (dd, J=13.3 Hz, 8.7 Hz, 1H), 3.60 (m, 1H),3.45 (m, 2H), 2.72 (d, J=5.0 Hz, 3H), 1.41 (s, 9H), 1.17 (d, J=6.9 Hz,3H). MS m/z (M+H): 511.1.

Example 119

Synthesis of(R)-3-((2-fluoro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-19)

To a solution of I-86 (302 mg, 0.66 mmol) in DMSO (15 mL), KF (383.3 mg,6.6 mmol) was added at room temperature. The resulting mixture wasstirred at 110° C. for 2 h. The reaction was partitioned between ethylacetate (20 mL) and water (30 mL), the organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×20 mL). Thecombined organic layers were washed with brine (50 mL) and the organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by reverse phase preparative HPLC (10-95%MeCN/Water, 0.1% TFA) afforded the desired product I-119 (24.4 mg, 8.4%)as a yellow solid. ¹H NMR (300 MHz, DMSO-d): δ 9.38 (d, J=9.3 Hz, 1H),8.20 (d, J=9.0 Hz, 1H), 8.14-8.12 (m, 1H), 7.86 (d, J=8.7 Hz, 10), 7.65(d, J=8.7 Hz, 1H), 7.15-7.10 (m, 1H), 5.04 (s, 4H), 3.68-3.55 (m, 1H),3.47-3.42 (m, 2H), 1.19 (d, J=6.6 Hz, 1H). MS m/z (M+H): 438.1.

Example 120

Synthesis of(R)-3-((5-((tert-butyl(methyl)amino)methyl)-2-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-120)

To a solution of I-80 (80.0 mg, 0.16 mmol) in DMSO (6 mL), KF (90.8 mg,1.57 mmol) was added at room temperature. The resulting reaction mixturewas stirred at 110° C. for 2 h. The reaction was cooled and thenpartitioned between ethyl acetate (20 mL) and water (30 mL), the organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic layer was washed with brine (50mL) and the organic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by reverse phaseprep-HPLC (10-95% MeCN/Water, 0.1% TFA) afforded the desired product,I-120 (10.4 mg, 12.8%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ9.35 (d, J=9.3 Hz, 1H), 8.70 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.15-8.11(m, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H). 7.17-7.15 (m,1H), 3.70-3.65 (m, 3H), 3.47-3.41 (m, 2H), 2.18 (s, 3H), 1.19 (d, J=6.3Hz, 3H), 1.13 (s, 9H). MS m/z (M+H): 495.2.

Example 121

Synthesis of(R)-3-((5-(ethoxymethyl)-2-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-121)

To a solution of I-82 (180 mg, 0.38 mmol) in DMSO (15 mL), KF (222.2 mg,3.8 mmol) was added at room temperature. The resulting reaction mixturewas stirred at 110° C. for 2 h. The reaction mixture was partitionedbetween ethyl acetate (20 mL) and water (30 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×20mL). The combined organic layer was washed with brine (50 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by reverse phasepreparative HPLC (10-95% MeCN/Water, 0.1% TFA) afforded the desiredproduct, I-121 (49.2 mg, 26.9%) as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ 9.33 (d, J=9.3 Hz, 1H), 8.72 (s, 1H), 8.19 (d, J=8.7 Hz,1H), 8.09-8.07 (m, 1H), 7.86 (d, J=9.3 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H),7.14-7.05 (m, 1H), 4.67 (s, 1H), 3.64-3.62 (m, 3H), 3.47-3.41 (m, 2H),1.23-1.18 (m, 6H). MS m/z (M+H): 454.1.

Example 122

Synthesis of(R)-3-(2-chloro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrmidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-122)

To a solution of INT-95 in THF (2 mL) and methanol (1 mL) was addedacetic acid (10.45 μL, 0.183 mmol) and formaldehyde (0.068 mL, 0.913mmol) (37% in water). After stirring for 10 min, sodiumtriacetoxyborohydride (58.0 mg, 0.274 mmol) was added. After 40 min, thereaction mixture was cooled to 0° C., quenched with sat. aq NaHCO₃,extracted with DCM-MeOH (4×, 9:1). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. Purification by HPLC(10-95% McCN/Water, 0.1% TFA) gave I-122 (9.0 mg, 0.018 mmol, 19%yield). ¹H NMR (400 MHz, DMSO-d_(b)): δ 9.90 (br, 1H), 9.38 (d, J=9.2Hz, 1H), 8.72 (s, 1H), 8.22-8.17 (m, 2H), 7.86 (d, J=9.2 Hz, 1H), 7.67(d, J=9.2 Hz, 1H), 7.18 (t, J=5.3 Hz, 1H), 6.38 (s, 1H), 4.10-3.74 (m,2H), 3.62-3.28 (m, 5H), 2.97-2.81 (m, SH), 1.19 (d, J=6.9 Hz, 3H). MSm/z (M+H): 507.0.

Example 123

Synthesis of(R)-3-((2-chloro-5-(pyridin-3-yl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-123)

To a suspension of I-116 (30.1 mg, 0.062 mmol) in anhydrous 1,4-dioxane(1.5 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (0.12 mL, 5 mol %, 0.025M inanhydrous 1,4-dioxane) at room temperature to give a light-brown slurrysolution. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.2mg, 0.074 mmol) in anhydrous 1,4-dioxane (0.2 mL) was added to theresulting solution and followed by the addition of Cs₂CO₃ (0.1 mL, 1.0 Min water). The resulting mixture was degassed with nitrogen and shakenat 80° C. on a shaker overnight. After cooling to room temperature andthe removal of solvents, the residue was dissolved in DMSO (3.0 mL) andfiltered. The filtered solution was purified by reverse phase HPLC(0.01% formic acid in Water-CH₃CN) to afford the desired product I-123(6.1 mg, 20.6%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (d,J=8.7 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.94 (s, 1H), 8.66 (dd, J=4.8,1.8 Hz, 1H), 8.21 (m, 1H), 8.16 (d, J=8.7 Hz, 1H), 8.13-8.14 (br,1H),7.82 (d, J=8.7 Hz. 1H), 7.71 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.2, 1.0Hz, 1H), 7.17 (t, J=5.7 Hz), 3.57-3.60 (m, 1H), 3.45-3.46 (m, 2H), 1.19(d, J=6.6 Hz, 3H). MS m/z (M+H): 489.4.

Example 124

Synthesis of(R)-3-((2-chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-124)

I-116 (180 mg, 0.367 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(154 mg, 0.733 mmol), PdCl₂(dppf) (0.027 g, 0.037 mmol), and potassiumcarbonate (152 mg, 1.100 mmol) were dissolved in 8 mL of dry DMF anddegassed by evacuation/sonication (2×) backfilling each time with argon.The reaction was then warmed to 85° C. with stirring. Once the reactionwas determined to be complete by LC/MS the mixture was cooled, pouredinto water, and extracted 3× with DCM. The combined organic layers weredried over sodium sulfate, filtered, and concentrated. The resultingresidue was purified by reverse phase HPLC to afford I-124 (16 mg, 0.032mmol, 8.84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (d, J=9.6 Hz, 1H),8.69 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 9.34 (m, 1H), 7.84 (d, J=9.6 Hz,1H), 7.65 (d, J=11 Hz, 1H), 7.17 (br, 1H), 6.43 (s, 1H), 4.23 (m, 1H),4.06 (m, 1H), 3.79 (t, J=6.0 Hz, 1H), 3.60 (t, J=5.5 Hz, 1H), 3.45 (m,1H), 2.03 (m, 1H), 1.19 (d, J=6.6 Hz, 3H).

Example 125

Synthesis of(R)-3-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-125)

INT-6 (50 mg, 0.167 mmol) was suspended in 10 mL of dry DMF and flushedwith nitrogen. Potassium carbonate (0.231 g, 1.670 mmol) was added andthe reaction was stirred at 90° C. for 10 min. To this mixture,tert-butyl2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (61mg, 0.200 mmol) was added and the reaction was stirred an additional 1hour at 90° C. Once the reaction was judged complete by LC/MS, themixture was poured into saturated NH₄Cl, extracted 3× with DCM. Thecombined DCM extracts were dried over sodium sulfate, filtered andconcentrated onto silica. The crude material was then purified by flashchromatography using a gradient of 0-30% MeOH in EtOAc. Theproduct-containing fractions were combined, concentrated and theresulting residue was then dissolved in TFA (1.162 ml, 15.08 mmol) andstirred I h at room temperature. Once complete the reaction wasconcentrated, treated with 3 mL of NHOH (aq.) and the resulting solidwas isolated by filtration, washed with water and dried under highvacuum to give I-125 as a yellow solid (68 mg, 87% yield). ¹H NMR (400MHz, DMSO-d6): δ 9.40 (d, J=8.0 Hz, 1H), 9.53 (br, 1H), 8.22 (d, J=9.2Hz, 1H), 8.18 (d, J=4.1 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H) 7.18 (br, 1H),4.45 (br, 1H), 3.62 (m, 11H), 3.56 (m, 2H), 3.46 (m, 2H), 3.12 (t, J=6.4Hz, 1H), 2.54 (s, 3H), 1.19 (d, 6.4 Hz, 3H). MS m/z (M+H): 466.6.

Example 126

Synthesis of(R)-3-((2-chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-126)

I-125 (0.1 g, 0.214 mmol) was dissolved in 3 mL of a 1:2 MeOH-THFmixture. Acetic acid (0.025 ml, 0.428 mmol) and formaldehyde (0.080 ml,1.071 mmol) were added and the reaction was stirred for 10 min thenSodium triacetoxyborohydride (0.136 g, 0.642 mmol) was added. Thereaction was allowed to stir for and additional hour at roomtemperature. Once complete, the reaction was diluted with 1 mL of water,concentrated and the resulting residue was dissolved in 4 mL of DMSO andpurified directly by reverse phase prep-HPLC (10-95% MeCN/Water, 0.1%TFA) to give I-126 (0.05 g, 49% yield). ¹H NMR (400 MHz, DMSO-d6): δ9.36 (d, J=11.4 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H),7.52 (d, J=9.2 Hz, 1H), 4.65 (br, 2H), 3.75 (m, 3H), 3.59 (m, 2H), 3.20(s, 3H), 1.32 (d, J=6.9 Hz, 3H). MS m/z (M+H): 480.8.

Example 127

Synthesis of(R)-3-((2-chloro-5-(hydroxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-127)

To a solution of INT-96 (60 mg, 0.1 mmol) in dimethylformamide (2.0 mL),tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 0.01 mmol) andtriethylsilane (72.4 mg, 0.6 mmol) were added at 0° C. The resultingreaction mixture was stirred at room temperature for 2 h. Aftercompletion, the reaction mixture was diluted with water (4.0 mL) andextracted with 10% methanol/dichlomethane (2×10 mL). The organic layerwas washed with water (5 mL) followed by saturated brine solution (5mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude material obtained waspurified by preparative HPLC to afford I-127 (22 mg, 40%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (d, J=6.8 Hz, 3H), 3.46 (br s,1H), 3.60 (br s, 1H), 4.68 (s, 2H), 5.66 (br s, 1H), 7.15 (t, J=5.2 Hz,1H), 7.60 (d, J=9.2 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 8.11 (d, J=4.4 Hz,1H), 8.17 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 9.35 (d, J=8.8 Hz, 1H). MSm/z (M+H): 442.4.

Example 128

Synthesis of(R)-3-((2-chloro-5-((4-hydroxypiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-128)

To a stirred suspension of INT-6 (150.0 mg, 0.5 mmol) in anhydrous DMF(7.5 mL) was added t-BuOK (1M in THF, 0.6 mL, 0.6 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-97 (144.5 mg, 0.55 mmol) inDMF (2 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (10 mL) and water (20 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×10mL). The combined organic layer was washed with brine (30 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by prep-HPLC affordedI-128 (30 mg, 11.4%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ9.35 (d, J=9.0 Hz, 1H), 8.68 (s, 1H), 8.19-8.12 (m, 2H), 7.84 (d, J=9.0Hz, 1H), 7.59 (d, J=9.3 Hz, 1H), 7.15 (t, J=2.4 Hz, 1H), 4.56 (d, J=4.2Hz, 1H), 3.63 (s, 3H), 3.47-3.45 (m, 3H), 2.81-2.71 (m, 2H), 2.30-2.11(m, 2H), 1.75-1.65 (m, 2H), 1.46-1.40 (m, 2H), 1.19 (d, J=6.6 Hz, 3H).MS m/z (M+H): 525.0.

Example 129

(R)-3-((2-chloro-5-((4-ethoxypiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-129)

To a stirred suspension of INT-6 (131.0 mg, 0.44 mmol) in anhydrous DMF(11 mL) was added t-BuOK (1 M in THF, 0.72 mL, 0.72 mmol) at 0° C.dropwise to give a brown solution. The resulting solution was stirredfor further 0.5 h at this temperature. INT-98 (128.0 mg, 0.44 mmol) inDMF (1 mL) was added dropwise to the above solution and stirredovernight at room temperature. The reaction mixture was partitionedbetween ethyl acetate (15 mL) and water (15 mL), the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (2×15mL). The combined organic layer was washed with brine (30 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Purification by prep-HPLC affordedI-129 (49.8 mg, 20.4%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ9.89 (brs, 1H), 9.39 (d, J=4.5 Hz, 1H), 8.88 (s, 1H), 8.23-8.14 (m, 2H),7.88 (d, J=4.4 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.20-7.05 (m, 1H),4.68-4.43 (m, 2H), 3.80-3.63 (m, 2H), 3.60-3.44 (m, 6H), 3.26-3.03 (m,2H), 2.27-2.17 (m, 1H), 2.16-1.88 (m, 2H), 1.76-1.56 (m, 1H), 1.21 (d,J=6.0 Hz, 3H), 1.19-1.02 (m, 3H). MS m/z (M+H): 553.

Example 130

Synthesis of(R)-3-((2-chloro-5-((4-(2-methoxyethoxy)piperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrabydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-130)

To a solution INT-6 (135.6 mg, 0.4 mmol) in DMF (20 mL) was addedpotassium carbonate (625.9 mg, 4.5 mmol) at room temperature and stirredat 90° C. for 10 min. To the resulting mixture, INT-99 (145.0 mg, 0.4mmol) was added at 90° C. The resulting reaction mixture was stirred at90° C. for 1 h. After completion, the reaction mixture was diluted withice cold water (15.0 mL), extracted with ethyl acetate (2×10 mL) andwashed with brine solution (30 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give crude material. The crude was purified by reverse phaseprep-HPLC (10-95% McCN/Water, 0.05% NH₄HCO₃) to afford I-130 (14.5 mg,6%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) 9.35 (d, J=9.0 Hz, 1H),8.69 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.84 (d, J=9.0Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.15 (t, J=5.4 Hz, 1H), 3.63-3.52 (m,3H), 3.52-3.39 (m, 7H), 3.23 (s, 3H), 2.78-2.74 (m, 2H), 2.26-2.19 (m,2H), 1.84-1.81 (m, 2H), 1.50-1.44 (m, 2H), 1.20 (d, J=5.4 Hz, 3H). MSm/z (M+H): 583.4.

Example 131

Synthesis of(R)-3-((2-chloro-5-((4-(2-fluoroethoxy)piperdin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-131)

To a solution INT-6 (54.4 mg, 0.2 mmol) in DMF) (10 mL) was addedpotassium tert-butoxide (1 M in THF, 0.4 mL, 0.4 mmol) at 0° C. andstirred for 10 min. To the resulting mixture, INT-100 (56.0 mg, 0.2mmol) was added at 0° C. The resulting reaction mixture was stirred at25° C. overnight. After completion, the reaction mixture was dilutedwith ice cold water (15.0 mL), extracted with ethyl acetate (2×10 mL)and washed with brine solution (30 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give crude material. The crude was purified by reverse phaseprep-HPLC (10-95% MeCN/Water, 0.05% NH₄HCO₃) to afford I-131 (19.3 mg,19%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (d, J=9.0 Hz,1H), 8.69 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.84 (d,J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.15 (t, J=5.4 Hz, 1H), 4.57 (t,J=3.9 Hz, 1H), 4.41 (t, J=3.9 Hz, 1H), 3.68 (t, J=4.2 Hz, 1H), 3.64 (s,3H), 3.58 (t, J=4.2 Hz, 1H), 3.47-3.43 (m, 2H), 3.36-3.33 (m, 1H),2.78-2.75 (m, 2H), 2.27-2.20 (m, 2H), 1.87-1.83 (m, 2H), 1.50-1.47 (m,2H), 1.20 (d, J=6.6 Hz, 3H). MS m/z (M+H): 571.0.

Example 132

Synthesis of(R)-3-((2-chloro-5-((4-(methoxy-d3)piperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-132)

To a solution INT-6 (107.2 mg, 0.4 mmol) in DMF (15 mL) was addedpotassium carbonate (495.0 mg, 3.6 mmol) at room temperature and stirredat 90° C. for 10 min. To the resulting mixture, INT-101 (100.0 mg, 0.4mmol) was added at 90° C. The resulting reaction mixture was stirred at90° C. for 1 h. After completion, the reaction mixture was diluted withice cold water (30.0 mL), extracted with ethyl acetate (2×20 mL) andwashed with brine solution (50 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give crude material. The crude was purified by reverse phaseprep-HPLC (10-95% McCN/Water, 0.05% NH₄HCO₃) to afford I-132 (7.6 mg,4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (d, J=9.0 Hz,1H), 8.69 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.84 (d,J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.15 (t, J=5.4 Hz, 1H), 3.64-3.53(m, 3H), 3.47-3.40 (m, 2H), 3.28-3.17 (m, 1H), 2.76-2.73 (m, 2H),2.27-2.24 (m, 2H), 1.87-1.83 (m, 2H), 1.47-1.44 (m, 2H), 1.20 (d, J=6.6Hz, 3H). MS m/z (M+H): 542.0.

Example 133

Synthesis of(R)₃-((2-chloro-5-((4-isopropoxypiperidin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-133)

To a solution INT-6 (147.6 mg, 0.5 mmol) in DMF (30.0 mL) was addedpotassium carbonate (681.5 mg, 5.0 mmol) at room temperature and stirredat 90° C. for 10 min. To the resulting mixture, INT-102 (150.0 mg, 0.5mmol) was added at 90° C. The resulting reaction mixture was stirred at90° C. for 1 h. After completion, the reaction mixture was diluted withice cold water (30.0 mL), extracted with ethyl acetate (2×20 mL) andwashed with brine solution (50 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give crude material. The crude was purified by reverse phaseprep-HPLC (10-95% MeCN/Water, 0.05% NH₄HCO₃) to afford I-133 (24.2 mg,10.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (d, J=9.3Hz, 1H), 8.67 (br, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.84(d, J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.15 (t, J=4.8 Hz, 1H),3.70-3.63 (m, 4H), 3.53-3.47 (m, 2H), 3.41-3.36 (m, 1H), 2.78-2.74 (m,2H), 2.26-2.19 (m, 2H), 1.79-1.63 (m, 2H), 1.44-1.41 (m, 2H), 1.20 (d,J=6.6 Hz, 3H), 1.05 (d, J=6.0 Hz, 6H). MS m/z (M+H): 567.1.

Example 134

Synthesis of(R)-3-((5-((4-(tert-butoxy)piperidin-1-yl)methyl)-2-chloropyrimidin-4-yl)oxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-134)

To a solution INT-6 (158.0 mg, 0.5 mmol) in DMF (20 mL) was addedpotassium carbonate (828.0 mg, 6.0 mmol) at 90° C. and stirred for 10min. To the resulting mixture, INT-103 (168.0 mg, 0.5 mmol) was addedand stirred at 90° C. for 1 h. After completion, the reaction mixturewas diluted with ice cold water (30.0 mL), extracted with ethyl acetate(2×20 mL) and washed with brine solution (50 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated underreduced pressure to give crude material. The crude was purified byreverse phase prep-HPLC (10-95% MeCN/Water, 0.05% NH₄HCO₃) to affordI-134 (11.7 mg, 4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35(d, J=9.3 Hz, 1H), 8.68 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.12-8.08 (m,1H), 7.84 (d, J=9.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.15 (t, J=4.8 Hz,1H), 3.68-3.55 (m, 3H), 3.54-3.40 (m, 3H), 2.76-2.73 (m, 2H), 2.27-2.24(m, 2H), 1.69-1.63 (m, 2H), 1.44-1.41 (m, 2H), 1.20 (d, J=6.6 Hz, 3H),1.13 (s, 9H). MS m/z (M+H): 581.2.

Example 135

Synthesis of(R)-3-((2-chloro-5-((ethoxy-d5)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one(I-135)

To a suspension of INT-6 (66 mg, 0.220 mmol) in DMF (3.0 mL) was addedpotassium carbonate (274 mg, 1.980 mmol) and the resulting mixture wasstirred at 90° C. for 10 min. Solution of INT-104 (56 mg, 0.264 mmol) inDMF (2.0 mL) was added. The resulting reaction mixture was stirred at90° C. for 4 h. After completion, the reaction mixture was filtered, andfiltrates were concentrated under reduced pressure. The crude materialobtained was purified by flash chromatography on a silica gel columneluting with 1% to 15% MeOH-EtOAc gradient to afford I-135 (68 mg, 65%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.34 (d, J=9.2Hz, 1H), 8.69 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.14 (d, J=4.6 Hz, 1H),7.84 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 7.16 (t, J=5.0 Hz, 1H),4.63 (s, 2H), 3.56-3.60 (m, 1H), 3.40-3.47 (m, 2H), 1.16 (d, J=6.9 Hz,3H). MS m/z (M+H): 475.1.

BIOLOGICAL EXAMPLES

Described below are in vitro assays used to measure the biologicalactivity of provided compounds as selective inhibitors of MK2.

Example 136 Mitogen-Activated Protein Kinase-Activated Protein Kinase 2Omnia Assay for Compound Potency Assessment:

The protocol below describes a continuous-read kinase assay optimized tomeasure potency of compounds against p38α activated, mitogen-activatedprotein kinase-activated protein kinase 2 (MAPKAP-K2 or MK2) enzyme.Further details of this assay are described by Life Technologies,Carlsbad, Calif. on their website at the following URL:http://tools.lifetechnologies.com/content/sfs/manuals/omnia_kinase_assay_man.pdf.

[Reagent] Used:

[MK-2]=0.4 nM, [ATP]=10 μM and

[ST3-Sox]=10 μM (ATP_(app)K_(M)=10 μM)

Briefly, 10× stock solutions of MK2 (PV3317, from Life Technologies),1.13×ATP (AS001A), and Sox conjugated peptide substrate, S/T3-Sox,(KZN1031) were prepared in IX kinase reaction buffer consisting of 20 mMTris, pH 7.5, 5 mM MgCl₂, 1 mM EGTA, 5 mM β-glycerophosphate, 5%glycerol (10× stock, KB001A) and 0.2 mM DTT (DS001A). Enzyme solution (5μL) was added to each of DMSO (5 μL) or serially diluted test compoundsprepared in DMSO in a Corning (#3574) 384-well, white, non-bindingsurface microtiter plate (Corning, N.Y.). Kinase reactions were startedwith the addition of 45 μL of the ATP-peptide substrate S/T3-Sox mix andmonitored every 71 seconds for 120 minutes at λ_(ex)360/λ_(em)485 in aSynergy H₄ plate reader from BioTek (Winooski, Vt.) at room temperature.

Background signals from the no enzyme control wells were subtracted fromall progress curves. The initial linear portions of the net progresscurves were fit according to a linear equation to yield the slope andpercentage of inhibition (% inhibition) at each compound concentration.The net progress curves obtained during the first two hours of reactionswere also fit according to an ascending single-exponential equation(Eq. 1) to yield k_(obs) values at each compound concentration. Plots of% Inhibition versus inhibitor concentrations were fit according to adose-response equation (Eq. 2) to generate IC₅₀ and Hill slope valueswhile plots of k_(obs) versus inhibitor concentration were fit accordingto Equation 3 (Eq. 3) to generate apparent k_(inact)/K₁ values using theGraphPad PRISM software (Version 6.00; GraphPad San Diego, Calif.).

$\begin{matrix}{\mspace{79mu} {{F = {V_{0}\frac{( {1 - {e\text{?}}} )}{k_{obs}}}}{\text{?}\text{indicates text missing or illegible when filed}}}} & ( {{Eq}.\mspace{14mu} 1} )\end{matrix}$

where F is the fluorescence intensity from the plate reader, V₀ is aconstant reflecting the relationship between the instrument readout andproduct concentration, t is time, e is Euler's number, and k is theobserved inactivation rate constant.

$\begin{matrix}{{\% \mspace{14mu} {Inhibition}} = \frac{100}{1 + ( \frac{{IC}_{50}}{\lbrack I\rbrack} )^{n}}} & ( {{Eq}.\mspace{14mu} 2} )\end{matrix}$

where % Inhibition is percentage of inhibition, IC₅₀ is half maximalinhibitory concentration, [I] is the inhibitor concentration, and n isthe Hill slope.

$\begin{matrix}{k_{obs} = {\frac{k_{inact}}{K_{1}}\frac{\lbrack I\rbrack}{2}}} & ( {{Eq}.\mspace{14mu} 3} )\end{matrix}$

where k_(obs) is the observed inactivation rate constant, k_(inact) isthe apparent inactivation rate constant, K₁ is the apparent inhibitionconstant, and [I] is the inhibitor concentration. Results from thisassay, showing IC₅₀(i.e. the concentration at which a test compoundinhibits substrate peptide phosphorylation 50%) are reported innanomolar. Potency results for the compounds tested are shown in Table Ain the column entitled “MK2 IC₅₀.”

Example 137 Mass Spectrometry Assay for Detecting Level of CovalentModification of MK2

Compounds I-1 through I-50 of the invention were assayed in a massspectrometric assay to measure their ability to covalently modify MK2protein. The procedure for this assay follows. Intact MK2 protein(Invitrogen, Cat. No. PR5320A) was incubated for 60 minutes at roomtemperature with a 10-fold excess of test compound to protein. Aliquotsof the resulting mixture (6 μL each) were diluted with 0.2%trifluoroacetic acid (TFA, 10 μL) prior to micro C4 ZipTipping directlyonto the MALDI target using sinapinic acid as the desorption matrix (10mg/ml in 0.1% TFA:acetonitrile 50:50, v/v). The centroid mass of thetarget protein in the control sample was compared with the centroid massof the target protein incubated with compound. A shift in the centroidmass of the treated protein compared to the untreated protein wasdivided by the molecular weight of the compound. This number correspondsto the percentage of modified protein (a measure of the proportion oftotal target protein covalently bound to the test compound) after onehour incubation. Results from this assay are reported in Table A underthe column “Mass Modification”.

Compounds I-51 through I-129 were assayed in a magnetic bead massspectrometric assay to measure their ability to covalently modify MK2protein. The procedure for this assay follows. MK2 protein (Invitrogen,Cat. No. PR5320A) was incubated for 60 minutes at room temperature witha 10-fold excess of test compound to protein. 3 μL of magnetic Ni-NTAbeads were added to the 6 μL aliquots of sample, washed, eluted with0.2% trifluoroacetic acid (TFA, 2 μL), and spotted directly onto theMALDI target using sinapinic acid as the desorption matrix (10 mg/ml in0.1% TFA:acetonitrile 50:50, v/v). The centroid mass of the targetprotein in the control sample was compared with the centroid mass of thetarget protein incubated with compound. A shift in the centroid mass ofthe treated protein compared to the untreated protein was divided by themolecular weight of the compound. This number corresponds to thepercentage of modified protein (a measure of the proportion of totaltarget protein covalently bound to the test compound) after one hourincubation. Results from this assay are reported in Table A under thecolumn “Mass Modification”.

Example 138 MK2 Cellular Assay—Detection of Total and Phospho-Hsp27(Serine 78) by MSD ELISA (Thp1)

Compounds of the invention were assayed in Thp-1 human acute monocyticleukemia cells to measure inhibition of MK2 activity. Thp-1 cells weregrown in culture medium containing RPMI/10% FBS (fetal bovineserum)/0.05 mM 2-mercaptoethanol. 72 hours prior to the assay, 8×10⁴cells per well were plated in a 96 well flat bottom plate along with 10ng/mL phorbol 12-myristate 13-acetate (PMA). Cells were cultured in anincubator at 37° C. until needed for the assay. Cell plate media wasreplaced with culture media just prior to assay while compound dilutionswere being made.

Stock solutions of test compound, 1 mM in DMSO, were prepared. 0.9 μl oftest compound was added to 300 μl cell media for a startingconcentration of 3000 nM. Three-fold serial dilutions (1:3) were made incell assay media until the final concentration of 0.15 nM. Cell platemedia was discarded, followed by addition of 100 μl of the compoundcontaining media. The resulting preparation was incubated at 37° C. for1 hour.

Test compound-containing cell assay media was removed and the cells werewashed once with cell assay media. Cell assay media containing 50 ng/mLLPS (lipopolysaccharide) was added to the each well and incubated for 45minutes. Following LPS incubation, the cells were washed once with PBS(phosphate-buffered saline) and lysed with 60 μl Cell Extraction Buffer(Invitrogen #FNN0011) plus protease and phosphatase inhibitors. Theplate was then stored at −80° C. until further analysis.

The MULTI-SPOT Phospho(Ser78)/Total HSP27 ELISA Assay kit was purchasedfrom Meso Scale Delivery (MSD; catalog #K15128D). MSD provides a platethat has been pre-coated with capture antibodies for phosphor-HSP27(Ser78) and total HSP27. The pre-coated MSD plate was blocked with 150μL/well of 3% BSA in MSD wash buffer. The preparation was placed on ashaker at room temperature for an hour. While the ELISA plate wasblocked, the cell assay plate stored at −80° C. was placed on a shakerat 4° C. for 1 hour to thaw. The blocked MSD plate was washed on a platewasher, tapping out the last bit of wash solution, followed by additionof 30 μl of the lysate from the cell assay plate. The preparation wascovered and incubated for 1 hour at room temperature. The lysate wasremoved, the plate was washed 3 times on a plate washer and the last bitof wash buffer was tapped out and replaced with 25 μl/well detectionantibody (anti-total HSP27 conjugated with an electrochemiluminescentcompound, MSD SULFO-TAG label, supplied in kit) made in 1% BSA/MSD washbuffer. The plate was incubated for 1 hour at room temperature on ashaker, followed by 3 washes. The last bit of wash buffer was tappedout. 150 μl/well 1× MSD read buffer was added (4× read buffer suppliedwith kit) and the plate was analyzed on the MSD SECTOR®Imager foranalysis. The SECTOR®Imager measures intensity of emitted light toprovide a quantitative measure of phosphorylated HSP27 (Ser78) and totalHSP27 present in the sample. The relative percent phosphoprotcin in asample is calculated by dividing the Phospho-HSP27 signal intensity overthe total HSP27 signal intensity measured in each well. A curve fittinganalysis was performed using Graph Pad Prism software to generate anEC₅₀ based on the inhibitory responses of the LPS-induced p-HSP27/totalHSP27 signal ratio's normalized to DMSO-treated controls (set at 100%signal intensity). Results from this assay, showing EC₅₀(i.e. theconcentration at which a test compound inhibits phosphorylation of Hsp27by 50%) are reported in nanomolar. Results from this assay are reportedin Table A under the column “pHSP27 signaling ECs.”

Table A shows data for selected compounds in various assays. Compoundshaving an activity designated as “A” provided an EC₅₀/C₅₀≤100 nM;compounds having an activity designated as “B” provided an EC₅₀/IC₅₀ of101-500 nM; compounds having an activity designated as “C” provided anEC₅₀/IC₅₀ of 501-999 nM; compounds having an activity designated as “D”provided an EC₅₀/IC₅₀ of ≥1000 nM. Compounds having an activitydesignated as “E” provided a mass modification of ≥70%; compounds havingan activity designated as “F” provided a mass modification of 31-69%;compounds having an activity designated as “G” provided a massmodification ≤30%.

TABLE A MK2 Mass pHSP27 signaling Number IC₅₀ Modification EC₅₀ I-1  A FA I-2  A G D I-3  A G D I-4  A G D I-5  A G D I-6  A G I-7  A F A I-8  AG D I-9  A E A I-10  A G B I-11  A F A I-12  C G I-13  D G D I-14  A G DI-15  A G D I-16  A E A I-17  A F D I-18  A F B I-19  A G I-20  A G DI-21  A G D I-22  A F C I-23  A G I-24  C G D I-25  A F A I-26  A E DI-27  A G A I-28  A E D I-29  A G D I-30  A E B I-31  D F D I-32  A F BI-33  C F D I-34  C G D I-35  B F C I-36  C G D I-37  A F B I-38  A G DI-39  A G B I-40  A G A I-41  A G B I-42  A G C I-43  A G C I-44  A G BI-45  A G D I-46  A F C I-47  A F B I-48  A F D I-49  A G B I-50  A F CI-51  A F A I-52  B F A I-53  A F B I-54  A E D I-55  B G D I-56  A E AI-57  A E A I-58  A E A I-59  A E C I-60  A F B I-61  A G D I-62  A E BI-63  A E A I-64  A E D I-65  A E B I-66  A F B I-67  A F B I-68  A E AI-69  A G I-70  A E A I-71  A E A I-72  A G D I-73  A G D I-74  A E AI-75  A E A I-76  A E D I-77  E I-78  E I-79  A E B I-80  A E A I-81  AE B I-82  B E B I-83  B E A I-84  B A I-85  B E A I-86  A E A I-87  B EA I-88  D F I-89  B E A I-90  B E A I-91  A E A I-92  B E A I-93  B E AI-94  B E D I-95  B E A I-96  B F A I-97  C F C I-98  B E B I-99  A AI-100 A E A I-101 A A I-102 A E A I-103 A E B I-104 C D I-105 A E BI-106 B A I-107 B E A I-108 B E B I-109 B I-110 B E A I-111 A E B I-112A E B I-113 B E A I-114 B E A I-115 B E D I-116 A E A I-117 A A I-118 CE B I-119 A F A I-120 B E B I-121 B F C I-122 A E B I-123 A A I-124 A EB I-125 A E A I-126 A E A I-127 B F C I-128 B E B I-129 B E A I-130 B EA I-131 A E A I-132 A E A I-133 B E A I-134 B E A I-135 B E B

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-70. (canceled)
 71. A compound of the following structure:

or a pharmaceutically acceptable salt thereof.
 72. A pharmaceuticalcomposition comprising the compound according to claim 71, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 73. Thepharmaceutical composition according to claim 72, wherein saidcomposition is formulated for parenteral administration.
 74. Thepharmaceutical composition according to claim 72, wherein said compoundis formulated for oral administration.